U.S. patent application number 17/410459 was filed with the patent office on 2022-04-14 for methods and compositions for genetic modulation of tumor microenvironments.
The applicant listed for this patent is HUYABIO International, LLC. Invention is credited to Reid P. BISSONNETTE, Rosemary M. CESARIO, Mireille GILLINGS, Robert GOODENOW, Farbod SHOJAEI.
Application Number | 20220110924 17/410459 |
Document ID | / |
Family ID | |
Filed Date | 2022-04-14 |
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United States Patent
Application |
20220110924 |
Kind Code |
A1 |
BISSONNETTE; Reid P. ; et
al. |
April 14, 2022 |
METHODS AND COMPOSITIONS FOR GENETIC MODULATION OF TUMOR
MICROENVIRONMENTS
Abstract
Provided herein is a therapy comprising an HDAC inhibitor
(HDACi), and/or a PD-L1 and/or a PD-1 inhibitor, and/or a CTLA-4
inhibitor. The combination therapy provided herein can be a kit or
the composition or a pharmaceutical composition. Also, provided
herein is a method of treating cancer using the combination
therapy.
Inventors: |
BISSONNETTE; Reid P.;
(Carlsbad, CA) ; CESARIO; Rosemary M.; (San Diego,
CA) ; GOODENOW; Robert; (San Diego, CA) ;
SHOJAEI; Farbod; (San Diego, CA) ; GILLINGS;
Mireille; (San Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
HUYABIO International, LLC |
San Diego |
CA |
US |
|
|
Appl. No.: |
17/410459 |
Filed: |
August 24, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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63070173 |
Aug 25, 2020 |
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International
Class: |
A61K 31/4406 20060101
A61K031/4406; A61K 39/395 20060101 A61K039/395; C07K 16/28 20060101
C07K016/28; A61P 35/00 20060101 A61P035/00 |
Claims
1. A method of configuring a tumor microenvironment in a patient in
need thereof to respond to an immune checkpoint inhibitor therapy,
the method comprising: administering to the patient a tumor
microenvironment configuring amount of a composition comprising a
compound of formula I, or a pharmaceutically acceptable salt
thereof: ##STR00009## wherein, A is phenyl or a heterocyclic group,
optionally substituted with 1 to 4 substituents selected from the
group consisting of halogen, --OH, --NH.sub.2, --NO.sub.2, --CN,
--COOH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4
alkylamino, C2-C4 acyl, C2-C4 acylamino, C1-C4 alkythio, C1-C4
perfluoroalkyl, C1-C4 perfluoroalkyloxy, C1-C4 alkoxycarbonyl,
phenyl, and a heterocyclic group; B is phenyl optionally
substituted with 1 to 3 substituents selected from the group
consisting of halogen, --OH, --NH.sub.2, --NO.sub.2, --CN, --COOH,
C1-C4 alkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino,
C2-C4 acyl, C2-C4 acylamino, C1-C4 alkylthio, C1-C4 perfluoroalkyl,
C1-C4 perfluoroalkyloxy, C1-C4 alkoxycarbonyl, and phenyl; Y is a
moiety comprising --CO-- which is linear and in which the distances
between the centroid of ring B (W1), the centroid of ring A (W2)
and an oxygen atom as a hydrogen bond acceptor in the moiety Y (W3)
are: W1-W2=about 6.0 .ANG., W1-W3=about 3.0 .ANG. to about 6.0
.ANG., and W2-W3=about 4.0 .ANG. to about 8.0 .ANG., respectively;
Z is a bond or C1-C4 alkylene, --O--, --S--, --NH--, --CO--,
--CS--, --SO--, or --SO.sub.2--; R.sup.1 and R.sup.2 are
independently hydrogen or C1-C4 alkyl; R.sup.3 is hydrogen or C1-C4
alkyl; R.sup.4 is hydrogen or --NH.sub.2; one of X.sup.1, X.sup.2,
X.sup.3, or X.sup.4 is halogen, --OH, --NH.sub.2, --NO.sub.2, --CN,
--COOH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4
alkylamino, C2-C4 acyl, C2-C4 acylamino, C1-C4 alkylthio, C1-C4
perfluoroalkyl, C1-C4 perfluoroalkyloxy, or C1-C4 alkoxycarbonyl
optionally substituted with halogen or C1-C4 alkyl, while the
others of X.sup.1, X.sup.2, X.sup.3, or X.sup.4 are independently
hydrogen, provided, however, that when R.sup.4 is hydrogen, one of
X.sup.1, X.sup.2, X.sup.3, or X.sup.4 is --NH.sub.2, an aminoalkyl
group or an alkylamino group.
2. The method of claim 1, wherein the compound of formula I is a
class I, class II, or both, selective histone deacetylase
inhibitor.
3. The method of claim 1, wherein the compound of formula I
comprises: ##STR00010## or a pharmaceutically acceptable salt
thereof.
4. The method of claim 1, wherein the administration of the
compound of formula I increases an expression of one or more immune
checkpoints in the tumor microenvironment.
5. The method of claim 1, wherein the method further comprises
administering to the patient an immune checkpoint inhibitor.
6. The method of claim 5, wherein the immune checkpoint inhibitor
comprises an inhibitor of VISTA, PD-L1, CTLA-4, PD-L2, B7-1 (CD80),
B7-2 (CD86), B7-H3 (CD276), B7-H2, B7-H4 (VTCN1), HVEM (CD270,
TNFRSF14), Galectin 9, Galectin3, CEACAM1 (CD66a), OX-2 (CD200),
PVR (CD155), PVRL2 (Nectin-2, CD112), FGL-1, PECAM-1, TSG-6, CD47,
Stabilin-1 (Clever-1), Neuropilin 1, Neuropilin 2, CD158 (family),
IGSF2 (CD101), CD155, GITRL, CD137L, OX40L, LIGHT, CD70, PD-1,
RGMB, CTLA-4 (CD152), BTLA, CD160, Tim-3, CD200R, TIGIT, CD112R
(PVRIG), LAG-3 (CD223), PECAM-1, CD44, SIRP alpha (CD172a), or a
combination thereof.
7. The method of claim 6, wherein the inhibitor comprises a small
molecule compound, a nucleic acid, a peptide, a protein, a
monoclonal antibody, a human antibody, a mouse antibody, a chimeric
antibody, a humanized antibody, or a chimeric humanized antibody, a
peptibody, a diabody, a minibody, a single-chain variable fragment
(ScFv), or a fragment or variant thereof.
8. The method of claim 4, wherein the one or more immune
checkpoints comprise PD-1, PD-L1, CTLA-4, CD86, CD276/B7-H3, CD244,
lymphocyte activation gene-3 (LAG-3), T cell immunoreceptor with Ig
and ITIM domains (TIGIT), ecto-5'-nucleotidase (NT5E/CD73), signal
regulatory protein .alpha. (SIRP.alpha.), nuclear factor of
activated T cells 4 (NFATC4), poliovirus receptor (CD155), or any
combination thereof.
9. The method of claim 8, wherein the one or more immune
checkpoints comprise CD276/B7-H3, CD244, NT5E/CD73, or any
combination thereof.
10. The method of claim 1, wherein the administration of the
compound of formula I increases an expression of one or more
adaptive immunity genes.
11. The method of claim 10, wherein the adaptive immunity genes
comprise 4-1BB/CD137, tumor necrosis factor .alpha. (TNF.alpha.),
interleukin 2 receptor alpha (IL2R.alpha.)/CD25, GZMB (granzyme B),
IRF4, and chemokine (C-X3-C motif) receptor 1 (CXC3R1), chemokine
(CXC motif) receptor 6 (CXCR6), CXCR3, or any combination
thereof.
12. The method of claim 10, wherein the expression of the adaptive
immunity genes is increased no later than seven days following an
initial administration of the compound of formula I to the
patient.
13. The method of claim 1, wherein the administration of the
compound of formula I increases an expression of one or more
natural killer (NK) cell function genes.
14. The method of claim 13, wherein the NK cell function genes
comprise GZMB, killer cell lectin like receptor D1 (KLRD1/CD94),
killer cell lectin like receptor C2 (NKG2c/KLRC2), natural killer
cell granule protein 7 (NKG7), killer cell lectin like receptor K1
(KLRK1), or any combination thereof.
15. The method of claim 1, wherein the administration of the
compound of formula I increases an expression of one or more MHC
class I genes.
16. The method of claim 15, wherein the MHC class I genes comprise
H2-D1, H2-K1, or both.
17. The method of claim 1, wherein the administration of the
compound of formula I increases an expression of one or more MHC
class II genes.
18. The method of claim 17, wherein the MHC class II genes comprise
H2-Aa, H2-Eb1, or both.
19. The method of claim 1, wherein configuring the tumor
microenvironment comprises increasing expression of one or more
immune checkpoints in the patient and the tumor microenvironment
configuring amount of the compound of formula I is an amount of the
compound of formula I sufficient to increase expression of one or
more immune checkpoints in the patient.
20. The method of claim 19, wherein increasing the expression of
one or more immune checkpoints comprises increasing the expression
of one or more of: PD-1, PD-L1, CTLA-4, CD86, CD276/B7-H3, CD244,
lymphocyte activation gene-3 (LAG-3), T cell immunoreceptor with Ig
and ITIM domains (TIGIT), ecto-5'-nucleotidase (NT5E/CD73), signal
regulatory protein .alpha. (SIRP.alpha.), nuclear factor of
activated T cells 4 (NFATC4), poliovirus receptor (CD155), or any
combination thereof.
21. The method of claim 1, wherein configuring the tumor
microenvironment comprises increasing an expression of one or more
adaptive immunity genes in the tumor microenvironment of the
patient and the tumor microenvironment configuring amount of the
compound of formula I is an amount of the compound of formula I
sufficient to increase expression of one or more adaptive immunity
genes in the tumor microenvironment in the patient.
22. The method of claim 21, wherein increasing expression of one or
more adaptive immunity genes comprises increasing expression of one
or more of: 4-1BB/CD137, tumor necrosis factor .alpha.
(TNF.alpha.), interleukin 2 receptor alpha (IL2R.alpha.)/CD25, GZMB
(granzyme B), IRF4, and chemokine (C-X3-C motif) receptor 1
(CXC3R1), chemokine (CXC motif) receptor 6 (CXCR6), CXCR3, or any
combination thereof.
23. A method of increasing an expression of one or more natural
killer (NK) cell function genes in a tumor microenvironment of a
patient, the method comprising administering to said patient a
natural killer (NK) cell function gene expression increasing amount
of a composition comprising a compound of formula I, or a
pharmaceutically acceptable salt thereof.
24. The method of claim 23, wherein the NK cell function genes
comprise GZMB, killer cell lectin like receptor D1 (KLRD1/CD94),
killer cell lectin like receptor C2 (NKG2c/KLRC2), natural killer
cell granule protein 7 (NKG7), killer cell lectin like receptor K1
(KLRK1), or any combination thereof.
25. The method of claim 1, wherein the method of configuring the
tumor microenvironment comprises increasing an expression of one or
more MHC class I genes in the tumor microenvironment of the patient
and the tumor microenvironment configuring amount of the compound
of formula I is an amount of the compound of formula I sufficient
to increase expression of one or more MHC Class I genes in the
tumor microenvironment of the patient.
26. The method of claim 25, wherein the MHC class I genes comprise
H2-D1, H2-K1, or both.
27. The method of claim 1, wherein the method of configuring the
tumor microenvironment comprises increasing an expression of one or
more MHC class II genes in the tumor microenvironment of the
patient and the tumor microenvironment configuring amount of the
compound of formula I is an amount of the compound of formula I
sufficient to increase expression of one or more MHC class II genes
in the tumor microenvironment of the patient.
28. The method of claim 27 wherein increasing the expression of one
or more MHC class II genes in the tumor microenvironment comprises
increasing the expression of H2-Aa, H2-Eb1, or both.
29. The method of claim 1, wherein the histone deacetylase
inhibitor is HBI-8000, vorinostat, romidepsin, panobinostat,
belinostat, entinostat, mocetinostat, givinostat, practinostat,
quisinostat, abexinostat, chr-3996, or AR-42.
30. The method claim 1, wherein the method further comprises
administering to the patient an immune checkpoint inhibitor.
31. The method of claim 30, wherein the immune checkpoint inhibitor
comprises an inhibitor of VISTA, PD-L1, CTLA-4, PD-L2, B7-1 (CD80),
B7-2 (CD86), B7-H3 (CD276), B7-H2, B7-H4 (VTCN1), HVEM (CD270,
TNFRSF14), Galectin 9, Galectin3, CEACAM1 (CD66a), OX-2 (CD200),
PVR (CD155), PVRL2 (Nectin-2, CD112), FGL-1, PECAM-1, TSG-6, CD47,
Stabilin-1 (Clever-1), Neuropilin 1, Neuropilin 2, CD158 (family),
IGSF2 (CD101), CD155, GITRL, CD137L, OX40L, LIGHT, CD70, PD-1,
RGMB, CTLA-4 (CD152), BTLA, CD160, Tim-3, CD200R, TIGIT, CD112R
(PVRIG), LAG-3 (CD223), PECAM-1, CD44, SIRP alpha (CD172a), or a
combination thereof.
32. The method of claim 1, wherein the tumor microenvironment
configuring amount of the compound of formula I is an amount
greater than about 5 mg per administration.
33. The method of claim 1, wherein the tumor microenvironment
configuring amount of the compound of formula I is an amount of
about 5 mg to about 50 mg per administration.
34. The method claim 1, further comprising administering an immune
checkpoint inhibitor in amount of about 0.1 mg/kg to about 30 mg/kg
per administration.
35. The claim 1, wherein the immune checkpoint inhibitor is present
at an amount of about 0.5 mg/kg to about 15 mg/kg.
36. The method of claim 1, wherein the tumor microenvironment
configuring amount of the compound of formula I is an amount
sufficient to increase of the expression of one or more immune
checkpoints, adaptive immunity genes, NK cell function genes, WIC
class I genes, MHC class II genes, or any combination thereof, and
the degree of inhibition of the one or more immune checkpoints,
adaptive immunity genes, NK cell function genes, MHC class I genes,
MHC class II genes is at least about 10%, about 20%, about 30%,
about 40%, about 50%, about 100%, about 150%, about 2 times, about
3 times, about 4 times, about 5 times, about 10 times, about 15
times, about 20 times, or about 25 times, relative to a tumor
microenvironment in a patient not administered the compound of
formula I.
37. A combination comprising a therapeutically effective amount of
a PD-1, PD-L1, or CTLA-4 inhibitor and a therapeutically effective
amount of a compound of formula I, or a pharmaceutically acceptable
salt thereof: ##STR00011## wherein, A is phenyl or a heterocyclic
group, optionally substituted with 1 to 4 substituents selected
from the group consisting of halogen, --OH, --NH.sub.2, --NO.sub.2,
--CN, --COOH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4
alkylamino, C2-C4 acyl, C2-C4 acylamino, C1-C4 alkythio, C1-C4
perfluoroalkyl, C1-C4 perfluoroalkyloxy, C1-C4 alkoxycarbonyl,
phenyl, and a heterocyclic group; B is phenyl optionally
substituted with 1 to 3 substituents selected from the group
consisting of halogen, --OH, --NH.sub.2, --NO.sub.2, --CN, --COOH,
C1-C4 alkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino,
C2-C4 acyl, C2-C4 acylamino, C1-C4 alkylthio, C1-C4 perfluoroalkyl,
C1-C4 perfluoroalkyloxy, C1-C4 alkoxycarbonyl, and phenyl; Y is a
moiety comprising --CO-- which is linear and in which the distances
between the centroid of ring B (W1), the centroid of ring A (W2)
and an oxygen atom as a hydrogen bond acceptor in the moiety Y (W3)
are: W1-W2=about 6.0 .ANG., W1-W3=about 3.0 .ANG. to about 6.0
.ANG., and W2-W3=about 4.0 .ANG. to about 8.0 .ANG., respectively;
Z is a bond or C1-C4 alkylene, --O--, --S--, --NH--, --CO--,
--CS--, --SO--, or --SO.sub.2--; R.sup.1 and R.sup.2 are
independently hydrogen or C1-C4 alkyl; R.sup.3 is hydrogen or C1-C4
alkyl; R.sup.4 is hydrogen or --NH.sub.2; one of X.sup.1, X.sup.2,
X.sup.3, or X.sup.4 is halogen, --OH, --NH.sub.2, --NO.sub.2, --CN,
--COOH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4
alkylamino, C2-C4 acyl, C2-C4 acylamino, C1-C4 alkylthio, C1-C4
perfluoroalkyl, C1-C4 perfluoroalkyloxy, or C1-C4 alkoxycarbonyl
optionally substituted with halogen or C1-C4 alkyl, while the
others of X.sup.1, X.sup.2, X.sup.3, or X.sup.4 are independently
hydrogen, provided, however, that when R.sup.4 is hydrogen, one of
X.sup.1, X.sup.2, X.sup.3, or X.sup.4 is --NH.sub.2, an aminoalkyl
group or an alkylamino group
38. The combination of claim 37, wherein the compound of formula I
is: ##STR00012## or a pharmaceutically acceptable salt thereof.
39. The combination of claim 37, wherein the compound of formula I
is
N-(2-amino-4-fluorophenyl)-4-[[[(2E)-1-oxo-3-(3-pyridinyl)-2-propen-1-yl]-
amino]methyl]benzamide.
40. The combination of claim 37, wherein the compound of formula I
is administered at an amount of greater than about 5 mg per
administration.
41. The combination of claim 37, wherein the compound of formula I
is administered at an amount of about 5 mg to about 50 mg per
administration.
42. The combination of claim 37, wherein the PD-1, PD-L1, or CTLA-4
inhibitor is a small molecule compound, a nucleic acid, a peptide,
a protein, a monoclonal antibody, a human antibody, a mouse
antibody, a chimeric antibody, a humanized antibody, or a chimeric
humanized antibody, a peptibody, a diabody, a minibody, a
single-chain variable fragment (ScFv), or a fragment or variant
thereof.
43. The combination of claim 37, wherein the PD-1, PD-L1, or CTLA-4
inhibitor is a humanized antibody comprising durvalumab, avelumab,
atezolizumab, or BMS-936559.
44. The combination of claim 37, wherein the PD-1, PD-L1, or CTLA-4
inhibitor is a humanized antibody administered at an amount of
about 0.1 mg/kg to about 30 mg/kg per administration.
45. The combination of claim 37, wherein the PD-1, PD-L1, or CTLA-4
inhibitor is a humanized antibody administered at an amount of
about 0.5 mg/kg to about 15 mg/kg per administration.
46. The combination of claim 37, wherein the PD-1, PD-L1, or CTLA-4
inhibitor is a humanized antibody administered at an amount of
about: 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 5 mg/kg, 10
mg/kg, or 20 mg/kg per administration.
47. The combination claim 37, wherein the combination is suitable
for administration to a cancer patient.
48. A pharmaceutical composition, comprising a combination of claim
37 and a pharmaceutically acceptable excipient.
49. A kit comprising the combination of claim 37 and optionally a
pharmaceutically acceptable excipient.
50. A method for treating cancer, the method comprising
administering to a cancer patient in need thereof a therapeutically
effective amount of a combination of claim 37.
51. The method of claim 50, wherein the cancer is a solid tumor
cancer selected from the group consisting of squamous cell
carcinoma, nonsquamous cell carcinoma, non-small cell lung cancer
(NSCLC), small cell lung cancer, melanoma, hepatocellular
carcinoma, renal cell carcinoma, ovarian cancer, head and neck
cancer, urothelial cancer, breast cancer, prostate cancer,
glioblastoma, colorectal cancer, pancreatic cancer, lymphoma,
leiomyosarcoma, liposarcoma, synovial sarcoma, or malignant
peripheral sheath tumor (MPNST).
52. The method of claim 50, wherein the cancer is non-small cell
lung cancer (NSCLC), hepatocellular carcinoma, melanoma, ovarian
cancer, breast cancer, pancreatic cancer, renal cell carcinoma, or
colorectal cancer.
53. The method of claim 50, wherein the cancer is lymphoma,
Non-Hodgkin's lymphoma (NHL), Hodgkin's Lymphoma, Reed-Sternberg
disease, multiple myeloma (MM), acute myelogenous leukemia (AML),
chronic myelogenous leukemia (CML), acute lymphocytic leukemia,
(ALL), or chronic lymphocytic leukemia (CLL).
54. The method of claim 50, wherein the cancer patient is treatment
naive.
55. The method of claim 54, wherein the cancer patient is treatment
naive for non-small cell lung cancer (NSCLC), hepatocellular
carcinoma, melanoma, ovarian cancer, breast cancer, pancreatic
cancer, renal cell carcinoma, or colorectal cancer.
56. The method of claim 50, wherein the compound of formula I is
administered to the cancer patient as a first line therapy.
57. The method of claim 50, wherein the compound of formula I is
administered to the cancer patient as a second, third, fourth,
fifth, or sixth line of treatment.
58. The method of claim 50, wherein the compound of formula I is
administered to the cancer patient following treatment with at
least one previous anti-cancer therapy.
59. The method of claim 58, wherein the at least one previous
anti-cancer therapy comprises chemotherapy, radiotherapy, surgery,
targeted therapy, immunotherapy, or a combination thereof.
60. The method of claim 50, wherein the cancer is resistant to at
least one anti-cancer agent.
61. The method of claim 50, wherein the compound of formula I and a
PD-1 inhibitor, a PD-L1 inhibitor, or a CTLA-4 inhibitor are
administered simultaneously or sequentially to the patient.
62. The method of claim 50, wherein the compound of formula I is
administered 2 to 3 times per week.
63. The method of claim 50, wherein the compound of formula I is
administered daily.
64. The method of claim 50, wherein a combination of a compound of
formula I and one or more of a PD-1 inhibitor, a PD-L1 inhibitor,
or a CTLA-4 inhibitor are administered on day 1 of an
administration regimen.
65. The method of claim 50, wherein the PD-1 inhibitor, the PD-L1
inhibitor, or the CTLA-4 inhibitor is a small molecule compound, a
nucleic acid, a peptide, a protein, an antibody, a peptibody, a
diabody, a minibody, a single-chain variable fragment (ScFv), or a
variant thereof.
66. The method claim 49, wherein the PD-1 inhibitor, the PD-L1
inhibitor, or the CTLA-4 inhibitor is a PD-1, PD-L1, or CTLA-4
inhibitor antibody.
67. The method of claim 66, wherein the PD-1, PD-L1, or CTLA-4
inhibitor antibody comprises one or more of durvalumab, avelumab,
atezolizumab, BMS-936559, STI-A1010, STI-A1011, STI-A1012,
STI-A1013, STI-A1014, or STI-A1015 (Sorrento Therapeutics).
68. The method of claim 66, wherein the PD-1, PD-L1, or CTLA-4
inhibitor antibody comprises one or more of durvalumab, avelumab,
atezolizumab, or BMS-936559.
69. The method of claim 50, wherein the combination is administered
to the patient as a regimen.
70. The method of claim 69, wherein the regimen is repeated until
disease progression or unacceptable toxicity.
71. The method of claim 69, wherein the regimen comprises a rest
period of at least 1 day between consecutive administration
periods.
72. The method of claim 69, wherein the compound of formula I of
the combination is administered 2 to 3 times per week in the
regimen and the PD-1, PD-L1, or CTLA-4 inhibitor antibody is
administered every 2 to 3 weeks.
73. The method of claim 69, wherein the compound of formula I of
the combination is administered QD for 21 days in the regimen and
the PD-1, PD-L1, or CTLA-4 inhibitor antibody is administered every
2 to 3 weeks.
74. The method of claim 50, wherein the method of treating cancer
inhibits metastasis of the cancer in the patient, reduces tumor or
tumor burden in the patient, inhibits pre-existing metastasis of
the cancer in the patient, prolongs the time to disease progression
of the cancer in the patient, prolongs the survival of the patient,
or increases progression-free survival of the patient.
75. A method for reducing a level of myeloid-derived suppressor
cells (MDSC) or regulatory T-cells (Treg cells) in a patient in
need thereof, enhancing the activity of a natural killer (NK) or
cytotoxic T-cell activity in-vivo, or enhancing antibody-dependent
cell-mediated cytotoxicity in a cancer patient, the method
comprising administering a therapeutically effective amount of a
combination of claim 37 to a patient in need thereof and
determining the level of MDSCs after the administration.
76. A method for treating cancer, comprising administering a
therapeutically effective amount of a combination of a histone
deacetylase inhibitor (HDACi) and a PD-1, PD-L1, or CTLA-4
inhibitor to a cancer patient in need of treatment and whose cancer
was previously treated with a prior therapy comprising
administration of one or more of a PD-1, PD-L1, and/or CTLA-4
inhibitor in the absence of the HDACi.
77. The method of claim 76, wherein the cancer, after treatment
with the prior therapy, exhibited partial response, but later
developed resistance to the prior therapy, with progression of
disease.
78. The method of claim 76, wherein the cancer, after treatment
with the prior therapy exhibited stable disease, but later
developed resistance to the prior therapy, with progression of
disease.
79. The method of claim 76, wherein the cancer, after treatment
with the prior therapy exhibited a complete response, but later
developed resistance to the prior therapy.
80. The method of claim 76, wherein the cancer, after treatment
with the prior therapy, exhibited no response to the prior
therapy.
81. The method of claim 76, wherein the PD-1, PD-L1, or CTLA-4
inhibitor is a small molecule compound, a nucleic acid, a peptide,
a protein, an antibody, a peptibody, a diabody, a minibody, a
single-chain variable fragment (ScFv), or a fragment or variant
thereof.
82. The method of claim 76, wherein the PD-1, PD-L1, or CTLA-4
inhibitor comprises an antibody.
83. The method of claim 82, wherein the antibody comprises one or
more of durvalumab, avelumab, atezolizumab, BMS-936559, STI-A1010,
STI-A1011, STI-A1012, STI-A1013, STI-A1014, or STI-A1015.
84. The method of claim 76, wherein the HDAC inhibitor comprises a
compound of formula I, or a pharmaceutically acceptable salt
thereof: ##STR00013## wherein, A is phenyl or a heterocyclic group,
optionally substituted with 1 to 4 substituents selected from the
group consisting of halogen, --OH, --NH.sub.2, --NO.sub.2, --CN,
--COOH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4
alkylamino, C2-C4 acyl, C2-C4 acylamino, C1-C4 alkythio, C1-C4
perfluoroalkyl, C1-C4 perfluoroalkyloxy, C1-C4 alkoxycarbonyl,
phenyl, and a heterocyclic group; B is phenyl optionally
substituted with 1 to 3 substituents selected from the group
consisting of halogen, --OH, --NH.sub.2, --NO.sub.2, --CN, --COOH,
C1-C4 alkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino,
C2-C4 acyl, C2-C4 acylamino, C1-C4 alkylthio, C1-C4 perfluoroalkyl,
C1-C4 perfluoroalkyloxy, C1-C4 alkoxycarbonyl, and phenyl; Y is a
moiety comprising --CO-- which is linear and in which the distances
between the centroid of ring B (W1), the centroid of ring A (W2)
and an oxygen atom as a hydrogen bond acceptor in the moiety Y (W3)
are: W1-W2=about 6.0 .ANG., W1-W3=about 3.0 .ANG. to about 6.0
.ANG., and W2-W3=about 4.0 .ANG. to about 8.0 .ANG., respectively;
Z is a bond or C1-C4 alkylene, --O--, --S--, --NH--, --CO--,
--CS--, --SO--, or --SO.sub.2--; R.sup.1 and R.sup.2 are
independently hydrogen or C1-C4 alkyl; R.sup.3 is hydrogen or C1-C4
alkyl; R.sup.4 is hydrogen or --NH.sub.2; one of X.sup.1, X.sup.2,
X.sup.3, or X.sup.4 is halogen, --OH, --NH.sub.2, --NO.sub.2, --CN,
--COOH, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4
alkylamino, C2-C4 acyl, C2-C4 acylamino, C1-C4 alkylthio, C1-C4
perfluoroalkyl, C1-C4 perfluoroalkyloxy, or C1-C4 alkoxycarbonyl
optionally substituted with halogen or C1-C4 alkyl, while the
others of X.sup.1, X.sup.2, X.sup.3, or X.sup.4 are independently
hydrogen, provided, however, that when R.sup.4 is hydrogen, one of
X.sup.1, X.sup.2, X.sup.3, or X.sup.4 is --NH.sub.2, an aminoalkyl
group or an alkylamino group.
85. The method of claim 76, wherein the HDAC inhibitor is
N-(2-amino-4-fluorophenyl)-4-[[[(2E)-1-oxo-3-(3-pyridinyl)-2-propen-1-yl]-
amino]methyl]benzamide.
86. The method of claim 76, wherein the HDAC inhibitor has the
following formula: ##STR00014## or a pharmaceutically acceptable
salt thereof.
87. The method of claim 76, wherein the HDAC inhibitor is selected
from one or more of the group consisting of vorinostat, romidepsin,
panobinostat, belinostat, entinostat, mocetinostat, givinostat,
practinostat, quisinostat, abexinostat, chr-3996, and AR-42.
88. The method of claim 76, wherein the cancer treated is one or
more of prostate, skin, ovarian cancer; cancers of non-lymphoid
parenchymal organs including the heart, placenta, skeletal muscle
and lung; breast cancer; cancers of the head and neck including
various lymphomas, such as mantle cell lymphoma, non-Hodgkins B
cell lymphoma, PTCL, adenoma, squamous cell carcinoma, laryngeal
carcinoma, salivary carcinoma, thymomas and thymic carcinoma;
leukemia; cancers of the retina; cancers of the esophagus; multiple
myeloma; melanoma; colorectal cancer; lung cancer; cervical cancer;
endometrium carcinoma; gallbladder cancer; liver cancer; thyroid
follicular cancer; gastric cancer; non-small cell lung carcinoma;
glioma; urotheial cancer; bladder cancer; prostate cancer; renal
cell cancer; infiltrating ductal carcinoma; and glioblastoma
multiform.
Description
[0001] This application claims priority under 35 U.S.C. .sctn. 119
(e) from U.S. provisional patent application No. 63/070,173, filed
Aug. 25, 2020, the contents of which are fully incorporated herein
by reference.
FIELD
[0002] The present invention relates to combinations of HDAC
inhibitors, PD-1 inhibitors, PD-L1 inhibitors, and CTLA-4
inhibitors, among other checkpoint inhibitors, and the use of such
combinations in the treatment of cancer.
BACKGROUND OF THE INVENTION
[0003] Cancer is a significant cause of morbidity and mortality
worldwide. While the standards of care for many different cancer
types have greatly improved over the years, current standards of
care still fail to meet the need for effective therapies to improve
treatment of cancer. The clinical use of immuno-oncology agents
targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and
the programmed cell death receptor-1 (PD-1) and its ligand PD-L1,
have resulted in improvements over the standard of care in the
treatment of many cancer types. While these checkpoint inhibitors
have produced improved clinical responses in such certain cancers,
durable clinical responses only occur in approximately 10-45% of
patients. Moreover, a significant number of tumors are either
resistant or become refractory. Epigenetic modifiers such as
histone deacetylase inhibitors (HDACi) have been successful in the
treatment of some hematologic malignancies, but despite preclinical
data demonstrating activity against solid tumors, this result has
not translated to the clinic as a monotherapy. Accordingly, there
is a need in the art for new therapies, including, for example,
combination therapies for the treatment of cancers. Provided herein
are solutions to these and other problems in the art.
SUMMARY OF THE INVENTION
[0004] Provided herein, inter alia, are combinations that include
an HDAC inhibitor (HDACi) and a PD-L1 and/or PD-1 inhibitor,
further in combination with a CTLA-4 inhibitor. The combinations
include a compound of formula I and a PD-L1 and/or PD-1 inhibitor,
further in combination with a CTLA-4 inhibitor. In certain
instances, the PD-L1 inhibitor, PD-1 inhibitor, and/or CTLA-4
inhibitor are antibodies. In some embodiments, the combination is
an HDAC inhibitor (HDACi) a PD-L1 inhibitor, and a CTLA-4
inhibitor. In some embodiments, the combination is an HDAC
inhibitor (HDACi) a PD-1 inhibitor, and a CTLA-4 inhibitor.
[0005] In a first aspect of the disclosure provided herein is a
combination comprising a therapeutically effective amount of a
PD-L1 inhibitor, a PD-1 inhibitor, a CTLA-4 inhibitor, a CD276
inhibitor, a therapeutically effective amount of a compound of
formula I, or any combination thereof, wherein formula I is:
##STR00001##
wherein, A is phenyl or a heterocyclic group, optionally
substituted with 1 to 4 substituents selected from the group
consisting of halogen, --OH, --NH.sub.2, --NO.sub.2, --CN, --COOH,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
aminoalkyl, C.sub.1-C.sub.4 alkylamino, C.sub.2-C.sub.4 acyl,
C.sub.2-C.sub.4 acylamino, C.sub.1-C.sub.4 alkythio,
C.sub.1-C.sub.4 perfluoroalkyl, C.sub.1-C.sub.4 perfluoroalkyloxy,
C.sub.1-C.sub.4 alkoxycarbonyl, phenyl, and a heterocyclic group; B
is phenyl optionally substituted with 1 to 3 substituents selected
from the group consisting of halogen, --OH, --NH.sub.2, --NO.sub.2,
--CN, --COOH, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 aminoalkyl, C.sub.1-C.sub.4 alkylamino,
C.sub.2-C.sub.4 acyl, C.sub.2-C.sub.4 acylamino, C.sub.1-C.sub.4
alkylthio, C.sub.1-C.sub.4 perfluoroalkyl, C.sub.1-C.sub.4
perfluoroalkyloxy, C.sub.1-C.sub.4 alkoxycarbonyl, and phenyl; Y is
a moiety comprising --CO-- which is linear and in which the
distances between the centroid of ring B (W1), the centroid of ring
A (W2) and an oxygen atom as a hydrogen bond acceptor in the moiety
Y (W3) are: W1-W2=about 6.0 .ANG., W1-W3=about 3.0 .ANG. to about
6.0 .ANG., and W2-W3=about 4.0 .ANG. to about 8.0 .ANG.,
respectively; Z is a bond or C.sub.1-C.sub.4 alkylene, --O--,
--S--, --NH--, --CO--, --CS--, --SO--, or --SO.sub.2--; R.sup.1 and
R.sup.2 are independently hydrogen or C.sub.1-C.sub.4 alkyl;
R.sup.3 is hydrogen or C.sub.1-C.sub.4 alkyl; R.sup.4 is hydrogen
or --NH.sub.2, one of X.sup.1, X.sup.2, X.sup.3, or X.sup.4 is
halogen, --OH, --NH.sub.2, --NO.sub.2, --CN, --COOH,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
aminoalkyl, C.sub.1-C.sub.4 alkylamino, C.sub.2-C.sub.4 acyl,
C.sub.2-C.sub.4 acylamino, C.sub.1-C.sub.4 alkylthio,
C.sub.1-C.sub.4 perfluoroalkyl, C.sub.1-C.sub.4 perfluoroalkyloxy,
or C.sub.1-C.sub.4 alkoxycarbonyl optionally substituted with
halogen or C.sub.1-C.sub.4 alkyl, while the others of X.sup.1,
X.sup.2, X.sup.3, or X.sup.4 are independently hydrogen, provided,
however, that when R.sup.4 is hydrogen, one of X.sup.1, X.sup.2,
X.sup.3, or X.sup.4 is --NH.sub.2, an aminoalkyl group or an
alkylamino group. In some embodiments, said compound of formula I
has the structure of formula Ia:
##STR00002##
In some embodiments, said compound of formula I is
N-(2-amino-4-fluorophenyl)-4-[[[(2E)-1-oxo-3-(3-pyridinyl)-2-propen-1-yl]-
amino]methyl]benzamide. In some embodiments, said PD-L1 inhibitor,
PD-1 inhibitor, CTLA-4 inhibitor, and/or CD276 inhibitor is a small
molecule compound, a nucleic acid, a peptide, a protein, an
antibody, a peptibody, a diabody, a minibody, a single-chain
variable fragment (ScFv), or a fragment or variant thereof. In some
embodiments, at least one of said PD-L1 inhibitor, PD-1 inhibitor,
CTLA-4 inhibitor, and/or CD276 inhibitor is an antibody. In some
embodiments, said inhibitor antibody is a monoclonal antibody. In
some embodiments, said inhibitor antibody comprises a human
antibody, a mouse antibody, a chimeric antibody, a humanized
antibody, or a chimeric humanized antibody. In some embodiments,
said inhibitor antibody is a human antibody or a humanized
antibody. In some embodiments, said inhibitor antibody is present
at an amount of about 0.1 mg/kg to about 30 mg/kg. In some
embodiments, said inhibitor antibody is present at an amount of
about 0.5 mg/kg to about 15 mg/kg. In some embodiments, said
inhibitor antibody is present at an amount of about: 0.1 mg/kg, 0.3
mg/kg, 1 mg/kg, 2 mg/kg, 2.5 mg/kg, 3 mg/kg, 5 mg/kg, 10 mg/kg, or
20 mg/kg. In some embodiments, said combination is suitable for
parenteral administration to a cancer patient. In some embodiments,
said parenteral administration comprises intravenous (IV)
administration.
[0006] Another aspect of the present disclosure comprises a
pharmaceutical composition comprising a combination of any one of
the embodiments described herein, and a pharmaceutically acceptable
excipient.
[0007] Another aspect of the present disclosure comprises a kit
comprising the combination of any of one of the embodiments
described herein or a pharmaceutical composition of the embodiments
described herein. In some embodiments, the kit further comprises at
least one administration device. In some embodiments, components in
the kit are sterilized.
[0008] Another aspect of the present disclosure comprises a method
for treating cancer, said method comprising administering a
therapeutically effective amount of a combination of any one of the
embodiments described herein or a pharmaceutical composition of the
embodiments described herein to a subject in need thereof. In some
embodiments, said subject has a mutated BRAF gene. In some
embodiments, said cancer is a solid tumor cancer selected from the
group consisting of squamous cell carcinoma, nonsquamous cell
carcinoma, non-small cell lung cancer (NSCLC), small cell lung
cancer, melanoma, hepatocellular carcinoma, renal cell carcinoma,
ovarian cancer, head and neck cancer, urothelial cancer, breast
cancer, prostate cancer, glioblastoma, colorectal cancer,
pancreatic cancer, lymphoma, leiomyosarcoma, liposarcoma, synovial
sarcoma, or malignant peripheral sheath tumor (MPNST). In some
embodiments, said cancer is non-small cell lung cancer (NSCLC),
hepatocellular carcinoma, melanoma, ovarian cancer, breast cancer,
pancreatic cancer, renal cell carcinoma, or colorectal cancer. In
some embodiments, said cancer is lymphoma, Non-Hodgkin's lymphoma
(NHL), Hodgkin's Lymphoma, Reed-Sternberg disease, multiple myeloma
(MM), acute myelogenous leukemia (AML), chronic myelogenous
leukemia (CML), acute lymphocytic leukemia, (ALL), or chronic
lymphocytic leukemia (CLL). In some embodiments, said cancer
patient is treatment naive. In some embodiments, said cancer
patient is treatment naive for non-small cell lung cancer (NSCLC),
hepatocellular carcinoma, melanoma, ovarian cancer, breast cancer,
pancreatic cancer, renal cell carcinoma, or colorectal cancer. In
some embodiments, said combination is administered to said cancer
patient as a first line therapy. In some embodiments, said
combination is administered to said cancer patient as a second,
third, fourth, fifth, or sixth line of treatment. In some
embodiments, said combination is administered to said cancer
patient following treatment with at least one anti-cancer therapy.
In some embodiments, said anti-cancer therapy comprises
chemotherapy, radiotherapy, surgery, targeted therapy,
immunotherapy, or a combination thereof. In some embodiments, said
cancer is resistant to at least one anti-cancer agent. In some
embodiments, said compound of formula I and said inhibitor of said
combination are administered simultaneously or sequentially. In
some embodiments, said compound of formula I is administered 2 to 3
times per week. In some embodiments, said compound of formula I is
administered daily. In some embodiments, said PD-L1 inhibitor, PD-1
inhibitor, CTLA-4 inhibitor, and/or CD276 inhibitor and said
compound of formula I are concomitantly administered on day 1 of an
administration regimen. In some embodiments, said combination is
administered to said patient as a regimen. In some embodiments,
said regimen is repeated until disease progression or unacceptable
toxicity. In some embodiments, said regimen comprises a rest period
of at least 1 day between consecutive administration periods. In
some embodiments, said compound of formula I of said combination is
administered 2 to 3 times per week in said regimen and said PD-L1
inhibitor, PD-1 inhibitor, CTLA-4 inhibitor, and/or CD276 inhibitor
is administered every 2 to 3 weeks. In some embodiments, said
compound of formula I of said combination is administered once a
day ("QD") for 21 days in said regimen and said inhibitor antibody
is administered every 2 to 3 weeks. In some embodiments, said
method of treating cancer inhibits metastasis of said cancer in
said patient. In some embodiments, said method of treating cancer
reduces tumor or tumor burden in said patient. In some embodiments,
said method of treating cancer inhibits pre-existing metastasis of
said cancer in said patient. In some embodiments, said method of
treating cancer prolongs the time to disease progression of said
cancer in said patient. In some embodiments, said method of
treating cancer prolongs the survival of said patient. In some
embodiments, said method of treating cancer increases
progression-free survival of said patient.
[0009] Another aspect of the present disclosure comprises a method
for treating cancer comprising administering a therapeutically
effective amount of a combination of a histone deacetylase
inhibitor (HDAC inhibitor) and a PD-L1 inhibitor and/or a PD-1
inhibitor, plus a CTLA-4 inhibitor, to a subject in need of
treatment and whose cancer has been previously treated with a
checkpoint inhibitor. A method for treating cancer comprising
administering a therapeutically effective amount of a PD-L1
inhibitor, a PD-1 inhibitor, a CTLA-4 inhibitor, a CD276 inhibitor,
a histone deacetylase inhibitor (HDAC inhibitor), or any
combination thereof, to a subject in need of treatment and whose
cancer has been previously treated with a checkpoint inhibitor.
[0010] Another aspect of the present disclosure comprises a method
for treating cancer comprising administering a therapeutically
effective amount of a PD-L1 inhibitor, a PD-1 inhibitor, a CTLA-4
inhibitor, a CD276 inhibitor, a histone deacetylase inhibitor (HDAC
inhibitor), or any combination thereof, to a subject in need of
treatment wherein said subject comprises a mutated BRAF gene. A
method for treating cancer comprising administering a
therapeutically effective amount of: a compound of formula I,
wherein formula I is:
##STR00003##
wherein, A is phenyl or a heterocyclic group, optionally
substituted with 1 to 4 substituents selected from the group
consisting of halogen, --OH, --NH.sub.2, --NO.sub.2, --CN, --COOH,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
aminoalkyl, C.sub.1-C.sub.4 alkylamino, C.sub.2-C.sub.4 acyl,
C.sub.2-C.sub.4 acylamino, C.sub.1-C.sub.4 alkythio,
C.sub.1-C.sub.4 perfluoroalkyl, C.sub.1-C.sub.4 perfluoroalkyloxy,
C.sub.1-C.sub.4 alkoxycarbonyl, phenyl, and a heterocyclic group; B
is phenyl optionally substituted with 1 to 3 substituents selected
from the group consisting of halogen, --OH, --NH.sub.2, --NO.sub.2,
--CN, --COOH, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 aminoalkyl, C.sub.1-C.sub.4 alkylamino,
C.sub.2-C.sub.4 acyl, C.sub.2-C.sub.4 acylamino, C.sub.1-C.sub.4
alkylthio, C.sub.1-C.sub.4 perfluoroalkyl, C.sub.1-C.sub.4
perfluoroalkyloxy, C.sub.1-C.sub.4 alkoxycarbonyl, and phenyl; Y is
a moiety comprising --CO-- which is linear and in which the
distances between the centroid of ring B (W1), the centroid of ring
A (W2) and an oxygen atom as a hydrogen bond acceptor in the moiety
Y (W3) are: W1-W2=about 6.0 .ANG., W1-W3=about 3.0 .ANG. to about
6.0 .ANG., and W2-W3=about 4.0 .ANG. to about 8.0 .ANG.,
respectively; Z is a bond or C.sub.1-C.sub.4 alkylene, --O--,
--S--, --NH--, --CO--, --CS--, --SO--, or --SO.sub.2--; R.sup.1 and
R.sup.2 are independently hydrogen or C.sub.1-C.sub.4 alkyl;
R.sup.3 is hydrogen or C.sub.1-C.sub.4 alkyl; R.sup.4 is hydrogen
or --NH.sub.2, one of X.sup.1, X.sup.2, X.sup.3, or X.sup.4 is
halogen, --OH, --NH.sub.2, --NO.sub.2, --CN, --COOH,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
aminoalkyl, C.sub.1-C.sub.4 alkylamino, C.sub.2-C.sub.4 acyl,
C.sub.2-C.sub.4 acylamino, C.sub.1-C.sub.4 alkylthio,
C.sub.1-C.sub.4 perfluoroalkyl, C.sub.1-C.sub.4 perfluoroalkyloxy,
or C.sub.1-C.sub.4 alkoxycarbonyl optionally substituted with
halogen or C.sub.1-C.sub.4 alkyl, while the others of X.sup.1,
X.sup.2, X.sup.3, or X.sup.4 are independently hydrogen, provided,
however, that when R.sup.4 is hydrogen, one of X.sup.1, X.sup.2,
X.sup.3, or X.sup.4 is --NH.sub.2, an aminoalkyl group or an
alkylamino group; and one or more inhibitor antibodies, wherein
said one or more inhibitor antibodies comprise a PD-L1 inhibitor, a
PD-1 inhibitor, a CTLA-4 inhibitor, a CD276 inhibitor, or any
combination thereof, and wherein said one or more inhibitor
antibodies are present at an amount of about 0.1 mg/kg to about 30
mg/kg; to a subject in need of treatment. In some embodiments, said
compound of formula I has the structure of formula Ia:
##STR00004##
In some embodiments, said compound of formula I is
N-(2-amino-4-fluorophenyl)-4-[[[(2E)-1-oxo-3-(3-pyridinyl)-2-propen-1-yl]-
amino]methyl]benzamide. In some embodiments, said one or more
inhibitor antibodies are monoclonal antibodies. In some
embodiments, said one or more inhibitor antibodies comprise a human
antibody, a mouse antibody, a chimeric antibody, a humanized
antibody, or a chimeric humanized antibody. In some embodiments,
said inhibitor antibody is a human antibody or a humanized
antibody. In some embodiments, said cancer is a solid tumor cancer
selected from the group consisting of squamous cell carcinoma,
nonsquamous cell carcinoma, non-small cell lung cancer (NSCLC),
small cell lung cancer, melanoma, hepatocellular carcinoma, renal
cell carcinoma, ovarian cancer, head and neck cancer, urothelial
cancer, breast cancer, prostate cancer, glioblastoma, colorectal
cancer, pancreatic cancer, lymphoma, leiomyosarcoma, liposarcoma,
synovial sarcoma, or malignant peripheral sheath tumor (MPNST). In
some embodiments, said cancer patient is treatment naive. In some
embodiments, said cancer patient is treatment naive for non-small
cell lung cancer (NSCLC), hepatocellular carcinoma, melanoma,
ovarian cancer, breast cancer, pancreatic cancer, renal cell
carcinoma, or colorectal cancer. In some embodiments, said
combination is administered to said cancer patient as a first line
therapy. In some embodiments, said combination is administered to
said cancer patient as a second, third, fourth, fifth, or sixth
line of treatment. In some embodiments, said combination is
administered to said cancer patient following treatment with at
least one anti-cancer therapy. In some embodiments, said
anti-cancer therapy comprises chemotherapy, radiotherapy, surgery,
targeted therapy, immunotherapy, or a combination thereof. In some
embodiments, said cancer is resistant to at least one anti-cancer
agent. In some embodiments, said compound of formula I and said
inhibitor of said combination are administered simultaneously or
sequentially. In some embodiments, said compound of formula I is
administered 2 to 3 times per week. In some embodiments, said
compound of formula I is administered daily. In some embodiments,
said PD-L1 inhibitor, PD-1 inhibitor, CTLA-4 inhibitor, and/or
CD276 inhibitor and said compound of formula I are concomitantly
administered on day 1 of an administration regimen. In some
embodiments, said PD-L1 inhibitor, PD-1 inhibitor, CTLA-4
inhibitor, and/or CD276 inhibitor and said compound of formula I
are administered to said patient as a regimen. In some embodiments,
said regimen is repeated until disease progression or unacceptable
toxicity. In some embodiments, said regimen comprises a rest period
of at least 1 day between consecutive administration periods. In
some embodiments, said compound of formula I is administered 2 to 3
times per week and said PD-L1 inhibitor, PD-1 inhibitor, CTLA-4
inhibitor, and/or CD276 inhibitor is administered every 2 to 3
weeks. In some embodiments, said compound of formula I of said
combination is administered once a day ("QD") for 21 days in said
regimen and said inhibitor antibody is administered every 2 to 3
weeks.
[0011] Another aspect of the present disclosure provides for a
combination that includes a therapeutically effective amount of 1)
a PD-L1 inhibitor and/or PD-1 inhibitor, 2) a therapeutically
effective amount of a CTLA-4 inhibitor, and 3) a therapeutically
effective amount of a compound of formula I:
##STR00005##
[0012] wherein A is phenyl or a heterocyclic group, optionally
substituted with 1 to 4 substituents selected from the group
consisting of halogen, --OH, --NH.sub.2, --NO.sub.2, --CN, --COOH,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
aminoalkyl, C.sub.1-C.sub.4 alkylamino, C.sub.2-C.sub.4 acyl,
C.sub.2-C.sub.4 acylamino, C.sub.1-C.sub.4 alkythio,
C.sub.1-C.sub.4 perfluoroalkyl, C.sub.1-C.sub.4 perfluoroalkyloxy,
C.sub.1-C.sub.4 alkoxycarbonyl, phenyl, and a heterocyclic
group,
[0013] wherein B is phenyl optionally substituted with 1 to 3
substituents selected from the group consisting of halogen, --OH,
--NH.sub.2, --NO.sub.2, --CN, --COOH, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 aminoalkyl, C.sub.1-C.sub.4
alkylamino, C.sub.2-C.sub.4 acyl, C.sub.2-C.sub.4 acylamino,
C.sub.1-C.sub.4 alkylthio, C.sub.1-C.sub.4 perfluoroalkyl,
C.sub.1-C.sub.4 perfluoroalkyloxy, C.sub.1-C.sub.4 alkoxycarbonyl,
and phenyl,
[0014] wherein Y is a moiety comprising --CO-- which is linear and
in which the distances between the centroid of ring B (W1), the
centroid of ring A (W2) and an oxygen atom as a hydrogen bond
acceptor in the moiety Y (W3) are: W1-W2=about 6.0 .ANG.,
W1-W3=about 3.0 .ANG. to about 6.0 .ANG., and W2-W3=about 4.0 .ANG.
to about 8.0 .ANG., respectively,
[0015] wherein Z is a bond or C.sub.1-C.sub.4 alkylene, --O--,
--S--, --NH--, --CO--, --CS--, --SO--, or --SO.sub.2--,
[0016] wherein R.sup.1 and R.sup.2 are independently hydrogen or
C.sub.1-C.sub.4 alkyl,
[0017] wherein R.sup.3 is hydrogen or C.sub.1-C.sub.4 alkyl,
and
[0018] wherein R.sup.4 is hydrogen or --NH.sub.2; and
[0019] wherein one of X.sup.1, X.sup.2, X.sup.3, or X.sup.4 is
halogen, --OH, --NH.sub.2, --NO.sub.2, --CN, --COOH,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
aminoalkyl, C.sub.1-C.sub.4 alkylamino, C.sub.2-C.sub.4 acyl,
C.sub.2-C.sub.4 acylamino, C.sub.1-C.sub.4 alkylthio,
C.sub.1-C.sub.4 perfluoroalkyl, C.sub.1-C.sub.4 perfluoroalkyloxy,
or C.sub.1-C.sub.4 alkoxycarbonyl optionally substituted with
halogen or C.sub.1-C.sub.4 alkyl, while the others of X.sup.1,
X.sup.2, X.sup.3, or X.sup.4 are independently hydrogen; provided,
however, that when R.sup.4 is hydrogen, one of X.sup.1, X.sup.2,
X.sup.3, or X.sup.4 is --NH.sub.2, an aminoalkyl group, or an
alkylamino group.
[0020] In one embodiment, the compound of formula I is
N-(2-amino-4-fluorophenyl)-4-[[[(2E)-1-oxo-3-(3-pyridinyl)-2-propen-1-yl]-
amino]methyl]benzamide, referred to herein as HBI-8000, or
chidamide.
[0021] In another embodiment, the PD-L1 inhibitor is a small
molecule compound, a nucleic acid, a peptide, a protein, an
antibody, a peptibody, a diabody, a minibody, a single-chain
variable fragment (ScFv), or a fragment or variant thereof
[0022] In still another embodiment, the PD-L1 inhibitor is an
antibody.
[0023] In yet another embodiment, the PD-L1 inhibitor antibody is
selected from durvalumab, avelumab, atezolizumab, BMS-936559,
STI-A1010, STI-A1011, STI-A1012, STI-A1013, STI-A1014, or STI-A1015
(Sorrento Therapeutics).
[0024] In another embodiment, the PD-1 inhibitor is a small
molecule compound, a nucleic acid, a peptide, a protein, an
antibody, a peptibody, a diabody, a minibody, a single-chain
variable fragment (ScFv), or a fragment or variant thereof
[0025] In still another embodiment, the PD-1 inhibitor is an
antibody.
[0026] In yet another embodiment, the PD-1 antibody is selected
from nivolumab, pembrolizumab, pidilizumab, REGN2810 (also known as
SAR-439684), PDR001, SHR-1210 or MEDI0680.
[0027] In another embodiment, the CTLA-4 inhibitor is a small
molecule compound, a nucleic acid, a peptide, a protein, an
antibody, a peptibody, a diabody, a minibody, a single-chain
variable fragment (ScFv), or a fragment or variant thereof.
[0028] In still another embodiment, the CTLA-4 inhibitor is an
antibody.
[0029] In yet another embodiment, the CTLA-4 antibody is
ipilimumab.
[0030] In another aspect is a pharmaceutical composition that
includes a combination described herein and a pharmaceutically
acceptable excipient.
[0031] In still another aspect is a kit that includes a combination
or a pharmaceutical composition as described herein.
[0032] In still another aspect is a method for treating cancer by
administering a therapeutically effective amount of a combination
or a pharmaceutical composition described herein to a patient in
need thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0033] The novel features of the invention are set forth with
particularity in the appended claims. A better understanding of the
features and advantages of the present invention will be obtained
by reference to the following detailed description that sets forth
illustrative embodiments, in which the principles of the invention
are utilized, and the accompanying drawings of which:
[0034] FIG. 1 shows median tumor volume amongst treatment groups
including a combination of compounds of formula I, a CTLA-4
inhibitory antibody, and a PD-1 inhibitory antibody. The dosing of
each treatment is indicated by the arrows below the graph.
[0035] FIG. 2 shows a Kaplan-Meier survival graph for the same
experimental groups from FIG. 1.
[0036] FIG. 3A shows the probability of progression free survival
("PFS") in terms of months resulting from a combination therapy
comprising compounds of formula I and Nivolumab in melanoma.
[0037] FIG. 3B shows the PFS for patients treated with Nivolumab
monotherapy, ipilimumab monotherapy, or a Nivolumab plus ipilimumab
combination therapy.
[0038] FIG. 4 shows checkpoint inhibitor ("CPI")-naive subjects
dosed with compounds of formula in combination with nivolumab.
[0039] FIG. 5 shows total time on treatment regime, termination
reason, and best ORR for melanoma subjects treated with compounds
of formula I and a PD-1 inhibitory antibody.
[0040] FIG. 6A shows immune gene activation in response to
administration of the compounds of formula I, a PD-1 inhibitory
antibody, and a combination of the compounds of formula I and a
PD-1 inhibitory antibody.
[0041] FIG. 6B shows improvement on survival amongst the
experimental group treated with the combination therapy compared to
the compounds of formula I alone or the PD-1 inhibitory antibody
alone.
[0042] FIG. 7A shows an estimated PFS for relapsed or refractory
peripheral T-cell lymphoma ("RR/PTCL") patients given the compounds
of formula I were used as a monotherapy.
[0043] FIG. 7B shows an estimated survival graph for relapsed or
refractory peripheral T-cell lymphoma ("RR/PTCL") patients given
the compounds of formula I were used as a monotherapy.
[0044] FIGS. 8A-8K shows Tumor growth inhibition (TGI) in mice
treated with ICI, HBI-8000, or their combination. Syngeneic MC38
(A-D), RENCA (E&F), CT26 (G&H), and A20 (I & J) tumors
were implanted in C57BL/6 or BALB/c mice, and allowed to grow until
the mean tumor volume was .about.100 mm3. Animals were then
randomized into groups with equivalent mean tumor volumes and
treated with the indicated therapeutic agents. Data shown in FIG.
8K represent the median tumor volume for each treatment group at
the indicated day post-initiation of therapy (FIGS. 8A, 8C, 8E, 8G,
and 8I), as well as the individual tumor volumes per animal (FIGS.
8B, 8D, 8F, 8H, and 8J).
[0045] FIGS. 9A-9B shows Immune cell-types and pathways modulated
by PD-1 Ab, HBI-8000, or their combination. Syngeneic MC38 tumors
were implanted in C57BL/6 mice and allowed to grow until the mean
tumor volume was .about.100 mm3. The mice were then randomized into
groups of 20 mice with equivalent mean tumor volumes and treated
with the indicated therapeutic agents. At days 7, 14, and 17,
groups of 20 mice were killed, and the tumors were excised, fixed
in formalin, and embedded in paraffin. Tumor sections were then
processed for nCounter gene expression analysis as described in the
Methods. FIG. 9A. Plots of the immune cell types in the TME
modulated by PD-1 Ab, HBI-8000, or their combination at days 7, 14,
and 17 for each treatment group. FIG. 9B. Immune checkpoints (PD1,
PD-L1, CTLA4, CD86, CD276, and CD244) modulated by PD-1 Ab,
HBI-8000, or their combination. The data depict the mRNA expression
levels for each gene at days 7, 14, and 17. Statistical
significance is as indicated in the graphs. Individual mice were
tagged according to the antitumor response. Red circles (.cndot.)
represent TGI>75%, inverted green triangles () TGI from 25%
through 75%, and blue squares (.quadrature.) were assigned to mice
with TGI<25%.
[0046] FIG. 10 shows Expression analyses of TNF.alpha., KLRD1,
CCR5, CCL2, CD137, and IRF4.
[0047] FIG. 11 shows TME immune response-relevant markers modulated
by PD-1 Ab, HBI-8000, or their combination. Expression of
IL-2R.alpha., CD8.alpha., CCR1, ENTPD1, GZMB, and PRF1 in tumors
isolated from mice in the Vehicle, HBI-8000, PD-1 Ab, and the
combination of HBI-8000 and PD-1 Ab groups.
[0048] FIG. 12 shows expression of cytokine/chemokine receptors,
MHC class I and class II are modulated by PD-1 Ab, HBI-8000, or
their combination. nCounter data analyses identified significant
differences in the expression of IL-7R, CXCR6, CX3CR1, CXCR3,
H2-Aa, H2-Eb1, H2-D1, and H2-K1 in tumors treated with PD-1 Ab,
HBI-8000, or their combination compared to the Vehicle-treated
group.
[0049] FIG. 13 shows ICI (PD-L1 Ab) plus HBI-8000 reverses
resistance to PD-1 Ab therapy and rescues mice with MC38 tumors
progressing on PD-1 Ab therapy. Mice implanted with MC38 tumors
were treated with PD-1 Ab as a first-line therapy for 18-21 days,
at which point mice displaying stable or slow tumor growth were
randomized into 1 of 6 second-line treatment groups, including
Vehicle, HBI-8000, PD-1 Ab, PD-1 Ab plus HBI-8000, PD-L1 Ab, and
PD-L1 Ab plus HBI-8000. Data shown represent individual tumor
volumes per animal in each treatment cohort.
[0050] FIGS. 14A-14B. FIG. 14A. shows a heatmap showing the raw
abundance of different immune cell types in the tumor
microenvironment (TME) modulated by PD-1 Ab, HBI-8000, or their
combination at day 17 for each tumor sample. Orange indicates high
abundance and blue indicates low abundance. FIG. 14B. shows a
heatmap of the directed global significance scores for immune
pathway types in the TME modulated by PD-1 Ab, HBI-8000, or their
combination at day 17 for each treatment group compared with the
control, as well as the directed global (all groups regardless of
treatment) significance scores for immune pathway types modulated
in nonresponders (TGI<25%) vs. responders (TGI>75%), and
partial responders (TGI<75%, >25%) vs. responders. Directed
global significance statistics measure the extent to which a gene
set's genes are upregulated or downregulated vs. the control. Red
denotes gene sets whose genes exhibit extensive overexpression with
the covariate, and blue denotes gene sets with extensive
underexpression. Left Y-axis depicts the various immune pathway
types.
[0051] FIG. 15 shows analysis of expression of LAG-3, TIGIT, NT5E,
SIRP.alpha., NFATC4, and CD155 in MC38 tumors treated with vehicle,
HBI-8000, PD-1 Ab, and the combination of HBI-8000 and PD-1 Ab
using the NanoString nCounter PanCancer Immune Profiling Panel, as
described in the FIG. 9 legend and in the Methods section.
[0052] FIG. 16 shows expression of CD40L, CD40, ICOS, NKG7, KLRC2,
and KLRK1 in MC38 tumors harvested from mice treated with vehicle,
HBI-8000, PD-1 Ab, and the combination of HBI-8000 and PD-1 Ab.
DETAILED DESCRIPTION
Definitions
[0053] All patents, applications, published applications and other
publications cited herein are incorporated by reference in their
entirety. Unless defined otherwise, all technical and scientific
terms used herein have the same meaning as commonly understood by
those of ordinary skill in the art to which the invention belongs.
The chemical structures and formulae set forth herein are
constructed according to the standard rules of chemical valency
known in the chemical arts. Should a discrepancy exist between a
depicted structure and a name given for that structure, the
depicted structure is to be accorded more weight. Where the
stereochemistry of a structure or a portion of a structure is not
indicated in a depicted structure or a portion of the depicted
structure, the depicted structure is to be interpreted as
encompassing all of its possible stereoisomers.
[0054] Any methods, devices and materials similar or equivalent to
those described herein can be used in the practice of this
invention. The following definitions are provided to facilitate
understanding of certain terms used frequently herein and are not
meant to limit the scope of the present disclosure. In the event
that there is a plurality of definitions for a term herein, those
in this section prevail unless stated otherwise. Headings used
herein are for organizational purposes only and in no way limit the
invention described herein.
[0055] The term "PD-L1 inhibitor" refers to a moiety (e.g.,
compound, nucleic acid, polypeptide, antibody) that decreases,
inhibits, blocks, abrogates or interferes with the activity,
binding of PD-L1 to its receptor, PD-1, or expression of PD-L1
(e.g., Programmed Cell Death 1 Ligand; PD-L1 (CD274); GI:
30088843), including variants, isoforms, species homologs of human
PD-L1 (e.g., mouse) and analogs that have at least one common
epitope with PD-L1. A PD-L1 inhibitor includes molecules and
macromolecules such as, for example, compounds (small molecule
compounds), nucleic acids, polypeptides, antibodies, peptibodies,
diabodies, minibodies, single-chain variable fragments (ScFv), and
fragments or variants thereof. Thus, a PD-L1 inhibitor as used
herein refers to any moiety that antagonizes PD-L1 activity, its
binding to PD-1, or its expression. PD-L1 inhibitor efficacy can be
measured, for example, by its inhibitor concentration at 50%
(half-maximal inhibitor concentration or IC.sub.50). PD-L1
inhibitors include exemplary compounds and compositions described
herein. A PD-L1 inhibitor antibody refers to a PD-L1 inhibitor
which is a monoclonal or polyclonal antibody as described
herein.
[0056] The terms "durvalumab," "avelumab," "atezolizumab,"
"BMS-936559," "STI-A1010," "STI-A1011," "STI-A1012," "STI-A1013,"
"STI-A1014," and "STI-A1015" are used in accordance with their
plain and ordinary meaning as understood in the art.
[0057] The term "PD-1 inhibitor" refers to a moiety (e.g.,
compound, nucleic acid, polypeptide, antibody) that decreases,
inhibits, blocks, abrogates or interferes with the activity or
expression of PD-1 (e.g., Programmed Cell Death Protein 1; PD-1
(CD279); GI: 145559515), including variants, isoforms, species
homologs of human PD-1 (e.g., mouse) and analogs that have at least
one common epitope with PD-1. A PD-1 inhibitor includes molecules
and macromolecules such as, for example, compounds, nucleic acids,
polypeptides, antibodies, peptibodies, diabodies, minibodies,
single-chain variable fragments (ScFv), and fragments or variants
thereof. Thus, a PD-1 inhibitor as used herein refers to any moiety
that antagonizes PD-1 activity or expression. PD-1 inhibitor
efficacy can be measured, for example, by its inhibitor
concentration at 50% (half-maximal inhibitor concentration or
IC.sub.50). PD-1 inhibitors include exemplary compounds and
compositions described herein. A PD-1 antibody refers to a PD-1
inhibitor which is a monoclonal or polyclonal antibody as described
herein.
[0058] The terms "nivolumab," "pembrolizumab," "pidilizumab,"
"AMP-224," "REGN2810," "PDR 001,", "SHR-1210", "SAR-439684" and
"MEDI0680" are used in accordance with their plain and ordinary
meaning as understood in the art.
[0059] The term "CTLA-4 inhibitor" refers to a moiety (e.g.,
compound, nucleic acid, polypeptide, antibody) that decreases,
inhibits, blocks, abrogates or interferes with the activity or
expression of CTLA-4, including variants, isoforms, species
homologs of human CTLA-4 (e.g., mouse) and analogs that have at
least one common epitope with CTLA-4. A CTLA-4 inhibitor includes
molecules and macromolecules such as, for example, compounds,
nucleic acids, polypeptides, antibodies, peptibodies, diabodies,
minibodies, single-chain variable fragments (ScFv), and fragments
or variants thereof. Thus, a CTLA-4 inhibitor as used herein refers
to any moiety that antagonizes CTLA-4 activity or expression.
CTLA-4 inhibitor efficacy can be measured, for example, by its
inhibitor concentration at 50% (half-maximal inhibitor
concentration or IC.sub.50). CTLA-4 inhibitors include exemplary
compounds and compositions described herein. A CTLA-4 antibody
refers to a CTLA-4 inhibitor which is a monoclonal or polyclonal
antibody as described herein.
[0060] The term "ipilimumab" is used in accordance with their plain
and ordinary meaning as understood in the art.
[0061] The term "CD276 inhibitor" refers to a moiety (e.g.,
compound, nucleic acid, polypeptide, antibody) that decreases,
inhibits, blocks, abrogates or interferes with the activity or
expression of CD276 (also referred to as B7-H3), including
variants, isoforms, species homologs of human CD276 (e.g., mouse)
and analogs that have at least one common epitope with CD276. A
CD276 inhibitor includes molecules and macromolecules such as, for
example, compounds, nucleic acids, polypeptides, antibodies,
peptibodies, diabodies, minibodies, single-chain variable fragments
(ScFv), and fragments or variants thereof. Thus, a CD276 inhibitor
as used herein refers to any moiety that antagonizes CD276 activity
or expression. CD276 inhibitor efficacy can be measured, for
example, by its inhibitor concentration at 50% (half-maximal
inhibitor concentration or IC.sub.50). CD276 inhibitors include
exemplary compounds and compositions described herein. A CD276
antibody refers to a CD276 inhibitor which is a monoclonal or
polyclonal antibody as described herein.
[0062] The terms "polypeptide" and "protein" are used
interchangeably herein and refer to any molecule that includes at
least 2 or more amino acids.
[0063] The term "Inhibitor Antibody" refers to a monoclonal or
polyclonal antibody that binds to its substrate or target with
sufficient strength to inhibit activity of the substrate or target.
As used herein, an Inhibitor Antibody comprises a PD-L1 inhibitor
antibody, PD-1 inhibitor antibody, CTLA-4 inhibitor antibody,
and/or CD276 inhibitor antibody.
[0064] The term "effective amount" refers to the amount of a
therapy (e.g., a combination provided herein or another active
agent such as an anti-cancer agent described herein) which is
sufficient to accomplish a stated purpose or otherwise achieve the
effect for which it is administered. An effective amount can be
sufficient to reduce and/or ameliorate the progression,
development, recurrence, severity and/or duration of a given
disease, disorder or condition and/or a symptom related thereto, or
can be sufficient to reduce the level of activity or binding of a
polypeptide (e.g., PD-L1, PD-1, CTLA-4). An effective amount can be
a "therapeutically effective amount" which refers to an amount
sufficient to provide a therapeutic benefit such as, for example,
the reduction or amelioration of the advancement or progression of
a given disease, disorder or condition, reduction or amelioration
of the recurrence, development or onset of a given disease,
disorder or condition, and/or to improve or enhance the
prophylactic or therapeutic effect(s) of another therapy. A
therapeutically effective amount of a composition described herein
can enhance the therapeutic efficacy of another therapeutic
agent.
[0065] The term "regimen" refers to a protocol for dosing and
timing the administration of one or more therapies (e.g.,
combinations described herein or another active agent such as an
anti-cancer agent described herein) for treating a disease,
disorder, or condition described herein. A regimen can include
periods of active administration and periods of rest as known in
the art. Active administration periods include administration of
combinations and compositions described herein and the duration of
time of efficacy of such combinations and compositions. Rest
periods of regimens described herein include a period of time in
which no compound is actively administered, and in certain
instances, includes time periods where the efficacy of such
compounds can be minimal. Combination of active administration and
rest in regimens described herein can increase the efficacy and/or
duration of administration of the combinations and compositions
described herein.
[0066] The terms "therapies" and "therapy" refer to any
protocol(s), method(s), and/or agent(s) that can be used in the
prevention, treatment, management, and/or amelioration of a
disease, disorder, or condition or one or more symptoms thereof. In
certain instances the term refers to active agents such as an
anti-cancer agent described herein. The terms "therapy" and
"therapy" can refer to anti-viral therapy, anti-bacterial therapy,
anti-fungal therapy, anti-cancer therapy, biological therapy,
supportive therapy, and/or other therapies useful in treatment,
management, prevention, or amelioration of a disease, disorder, or
condition or one or more symptoms thereof known to one skilled in
the art, for example, a medical professional such as a
physician.
[0067] The term "patient" or "subject" refers to a mammal, such as
a human, bovine, rat, mouse, dog, monkey, ape, goat, sheep, cow, or
deer. Generally a patient as described herein is human.
[0068] The terms "inhibition", "inhibit", "inhibiting" refer to a
reduction in the activity, binding, or expression of a polypeptide
or reduction or amelioration of a disease, disorder, or condition
or a symptom thereof. Inhibiting as used here can include partially
or totally blocking stimulation, decreasing, preventing, or
delaying activation or binding, or inactivating, desensitizing, or
down-regulating protein or enzyme activity or binding.
[0069] Antibodies described herein can be polyclonal or monoclonal
and include xenogeneic, allogeneic, or syngeneic forms and modified
versions thereof (e.g., humanized or chimeric). An "antibody" is
intended to mean a polypeptide product of B cells within the
immunoglobulin class of polypeptides that is able to bind to a
specific molecular antigen and is composed of two identical pairs
of polypeptide chains, wherein each pair has one heavy chain (about
50-70 kDa) and one light chain (about 25 kDa) and each
amino-terminal portion of each chain includes a variable region of
about 100 to about 130 or more amino acids and each
carboxy-terminal portion of each chain includes a constant region
(See Borrebaeck (ed.) (1995) Antibody Engineering, Second Edition,
Oxford University Press.; Kuby (1997) Immunology, Third Edition,
W.H. Freeman and Company, New York). Specific molecular antigens
that can be bound by an antibody described herein include PD-L1,
PD-1, CTLA-4, and their epitopes.
[0070] The term "monoclonal antibody(ies)" refers to a population
of antibody molecules that contain one species of an antigen
binding site capable of immunoreacting with a particular epitope of
an antigen, whereas the term "polyclonal antibody(ies)" refers to a
population of antibody molecules that contain multiple species of
antigen binding sites capable of interacting with a particular
antigen. A monoclonal antibody, typically displays a single binding
affinity for a particular antigen with which it immunoreacts. For
example, the monoclonal antibodies to be used in accordance with
the present invention can be made by a variety of techniques,
including, for example, the hybridoma method (e.g., Kohler and
Milstein, Nature, 256:495-97 (1975); Hongo et al., Hybridoma, 14
(3): 253-260 (1995), Harlow et al., Antibodies: A Laboratory
Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988);
Hammerling et al., in: Monoclonal Antibodies and T-Cell Hybridomas
563-681 (Elsevier, N.Y., 1981)), recombinant DNA methods (see,
e.g., U.S. Pat. No. 4,816,567), phage-display technologies (see,
e.g., Clackson et al., Nature, 352: 624-628 (1991); Marks et al., J
Mol. Biol. 222: 581-597 (1992); Sidhu et al., J. Mal. Biol. 338(2):
299-310 (2004); Lee et al., J. Mal. Biol. 340(5): 1073-1093 (2004);
Fellouse, Proc. Natl. Acad. Sci. USA 101(34): 12467-12472 (2004);
and Lee et al., J. Immunol. Methods 284(1-2): 119-132 (2004), and
technologies for producing human or human-like antibodies in
animals that have parts or all of the human immunoglobulin loci or
genes encoding human immunoglobulin sequences (see, e.g., WO
1998/24893; WO 1996/34096; WO 1996/33735; WO 1991/10741; Jakobovits
et al., Proc. Natl. Acad. Sci. USA 90: 2551 (1993); Jakobovits et
al., Nature 362: 255-258 (1993); Bruggemann et al., Year in
Immunol. 7:33 (1993); U.S. Pat. Nos. 5,545,807; 5,545,806;
5,569,825; 5,625,126; 5,633,425; and U.S. Pat. No. 5,661,016; Marks
et al., Bio/Technology 10: 779-783 (1992); Lon berg et al., Nature
368: 856-859 (1994); Morrison, Nature 368: 812-813 (1994); Fishwild
et al., Nature Biotechnol. 14: 845-851 (1996); Neuberger, Nature
Biotechnol. 14: 826 (1996); and Lonberg and Huszar, Intern. Rev.
Immunol. 13: 65-93 (1995).
[0071] The monoclonal antibodies herein also include "chimeric"
antibodies (immunoglobulins) in which a portion of the heavy and/or
light chain is identical with or homologous to corresponding
sequences in antibodies derived from a particular species or
belonging to a particular antibody class or subclass, while the
remainder of the chain(s) is(are) identical with or homologous to
corresponding sequences in antibodies derived from another species
or belonging to another antibody class or subclass, as well as
fragments of such antibodies, so long as they exhibit the desired
biological activity (U.S. Pat. No. 4,816,567; Morrison et al.,
Proc. Natl. Acad. Sci. USA, pp. 6851-6855 (1984)). "Humanized
antibody(ies)" can be considered as a subset of chimeric antibodies
described herein.
[0072] The term "human" when used in reference to an antibody or a
functional fragment thereof (e.g., "humanized antibody(ies))"
refers an antibody or functional fragment thereof that has a human
variable region or a portion thereof corresponding to human
germline immunoglobulin sequences. Such human germline
immunoglobulin sequences are described by Kabat et al. (1991)
Sequences of Proteins of Immunological Interest, Fifth Edition,
U.S. Department of Health and Human Services, NIH Publication No.
91-3242. A human antibody, in the context of the present invention,
can include an antibody that binds to PD-L1 or variants thereof as
described herein.
[0073] In certain instances a human antibody is an antibody that
possesses an amino acid sequence corresponding to that of an
antibody produced by a human and/or has been made using any of the
techniques for making human antibodies as disclosed herein. Human
antibodies can be produced using various techniques known in the
art, including phage-display libraries. Hoogenboom and Winter, J.
Mol. Biol., 227:381 (1991); Marks et al., J. Mal. Biol., 222:581
(1991). Also available for the preparation of human monoclonal
antibodies are methods described in Cole et al., Monoclonal
Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1 985); Boemer
et al., J. Immunol., 147(1):86-95 (1991). See also van Dijk and van
de Winkel, Curr. Opin. Pharmacol., 2:368-74 (2001). Human
antibodies can be prepared by administering the antigen to a
transgenic animal that has been modified to produce such antibodies
in response to antigenic challenge, but whose endogenous loci have
been disabled, e.g., immunized xenomice (see, e.g., U.S. Pat. Nos.
6,075.181 and 6, 150,584 regarding XENOMOUSE technology). See also,
for example, Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562
(2006) regarding human antibodies generated via a human B-cell
hybridoma technology.
[0074] A "humanized antibody" refers to antibodies made by a
non-human cell having variable or variable and constant regions
which have been altered to more closely resemble antibodies that
would be made by a human cell. For example, by altering the
non-human antibody amino acid sequence to incorporate amino acids
found in human germline immunoglobulin sequences. The humanized
antibodies of the invention can include amino acid residues not
encoded by human germline immunoglobulin sequences (e.g., mutations
introduced by random or site-specific mutagenesis in vitro or by
somatic mutation in vivo), for example in the CDRs. Humanized
antibodies can also include antibodies in which CDR sequences
derived from the germline of another mammalian species, such as a
mouse, have been grafted onto human framework sequences.
[0075] Humanized forms of non-human (e.g., murine) antibodies are
antibodies that contain minimal sequence derived from non-human
immunoglobulin. In one embodiment, a humanized antibody is a human
immunoglobulin (recipient antibody) in which residues from a
hypervariable region of the recipient are replaced by residues from
an hypervariable region of a nonhuman species (donor antibody) such
as mouse, rat, rabbit or non-human primate having the desired
specificity, affinity, and/or capacity. In some instances,
framework ("FR") residues of the human immunoglobulin are replaced
by corresponding non-human residues. Furthermore, humanized
antibodies can comprise residues that are not found in the
recipient antibody or in the donor antibody. These modifications
can be made to further refine antibody performance, such as binding
affinity. In general, a humanized antibody will comprise
substantially all of at least one, and typically two, variable
domains, in which all or substantially all of the hypervariable
loops correspond to those of a non-human immunoglobulin sequence,
and all or substantially all of the FR regions are those of a human
immunoglobulin sequence, although the FR regions can include one or
more individual FR residue substitutions that improve antibody
performance, such as binding affinity, isomerization,
immunogenicity, etc. The number of these amino acid substitutions
in the FR are typically no more than 6 in the H chain, and in the L
chain, no more than 3. The humanized antibody optionally can also
include at least a portion of an immunoglobulin constant region
(Fc), which can be a human immunoglobulin. Exemplary methods and
humanized antibodies include those described by Jones et al. Nature
321:522-525 (1986); Riechmann et al. Nature 332:323-329 (1988); and
Presta, Curr. Op. Struct. Biol. 2:593-596 (1992); Vaswani and
Hamilton, Ann. Allergy. Asthma & Immunol. 1:105-115 (1998);
Harris, Biochem. Soc. Transactions 23:1035-1038 (1995); Burle and
Gross, Curr. Op. Biotech. 5:428-433 (1994); and U.S. Pat. Nos.
6,982,321 and 7,087,409.
[0076] The term "functional fragment" when used in reference to an
antibody refers to a portion of the antibody including heavy or
light chain polypeptides that retains some or all of the binding
activity as the antibody from which the fragment was derived. Such
functional fragments can include, for example, an Fd, Fv, Fab,
F(ab'), F(ab).sub.2, F(ab').sub.2, single chain Fv (ScFv), diabody,
triabody, tetrabody and minibody. Other functional fragments can
include, for example, heavy or light chain polypeptides, variable
region polypeptides or CDR polypeptides or portions thereof so long
as such functional fragments retain binding activity. Such antibody
binding fragments can be found described in, for example, Harlow
and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor
Laboratory, New York (1989); Myers (ed.), Molec. Biology and
Biotechnology: A Comprehensive Desk Reference, New York: VCH
Publisher, Inc.; Huston et al., Cell Biophysics, 22:189-224 (1993);
Phickthun and Skerra, Meth. Enzymol., 178:497-515 (1989) and in
Day, E.D., Advanced Immunochemistry, Second Ed., Wiley-Liss, Inc.,
New York, N.Y. (1990). Antibody Engineering, Second Edition, Oxford
University Press, 1995.
[0077] The term "heavy chain" when used in reference to an antibody
refers to a polypeptide chain of about 50-70 kDa, wherein the
amino-terminal portion includes a variable region of about 120 to
130 or more amino acids and a carboxy-terminal portion that
includes a constant region. The constant region can be one of five
distinct types, referred to as alpha (.alpha.), delta (.delta.),
epsilon (.epsilon.), gamma (.gamma.) and mu (.mu.), based on the
amino acid sequence of the heavy chain constant region. The
distinct heavy chains differ in size: .alpha., .delta. and .gamma.
contain approximately 450 amino acids, while .mu. and .epsilon.
contain approximately 550 amino acids. When combined with a light
chain, these distinct types of heavy chains give rise to five well
known classes of antibodies, IgA, IgD, IgE, IgG and IgM,
respectively, including four subclasses of IgG, namely IgG1, IgG2,
IgG3 and IgG4. A heavy chain can be a human heavy chain.
[0078] The term "light chain" when used in reference to an antibody
refers to a polypeptide chain of about 25 kDa, wherein the
amino-terminal portion includes a variable region of about 100 to
about 110 or more amino acids and a carboxy-terminal portion that
includes a constant region. The approximate length of a light chain
is 211 to 217 amino acids. There are two distinct types, referred
to as kappa (.kappa.) of lambda (.lamda.) based on the amino acid
sequence of the constant domains. Light chain amino acid sequences
are well known in the art. A light chain can be a human light
chain.
[0079] The term "variable domain" or "variable region" refers to a
portion of the light or heavy chains of an antibody that is
generally located at the amino-terminal of the light or heavy chain
and has a length of about 120 to 130 amino acids in the heavy chain
and about 100 to 110 amino acids in the light chain, and are used
in the binding and specificity of each particular antibody for its
particular antigen. The variable domains can differ extensively in
sequence between different antibodies. The variability in sequence
is concentrated in the CDRs while the less variable portions in the
variable domain are referred to as framework regions (FR). The CDRs
of the light and heavy chains are primarily responsible for the
interaction of the antibody with antigen. Numbering of amino acid
positions used herein is according to the EU Index, as in Kabat et
al. (1991) Sequences of proteins of immunological interest. (U.S.
Department of Health and Human Services, Washington, D.C.) 5.sup.th
Ed. A variable region can be a human variable region.
[0080] A CDR refers to one of three hypervariable regions (H1, H2
or H3) within the non-framework region of the immunoglobulin (Ig or
antibody) VH .beta.-sheet framework, or one of three hypervariable
regions (L1, L2 or L3) within the non-framework region of the
antibody VL .beta.-sheet framework. Accordingly, CDRs are variable
region sequences interspersed within the framework region
sequences. CDR regions are well known to those skilled in the art
and have been defined by, for example, Kabat as the regions of most
hypervariability within the antibody variable (V) domains (Kabat et
al., J. Biol. Chem. 252:6609-6616 (1977); Kabat, Adv. Prot. Chem.
32:1-75 (1978)). CDR region sequences also have been defined
structurally by Chothia as those residues that are not part of the
conserved .beta.-sheet framework, and thus are able to adapt
different conformations (Chothia and Lesk, J. Mol. Biol.
196:901-917 (1987)). Both terminologies are well recognized in the
art. The positions of CDRs within a canonical antibody variable
domain have been determined by comparison of numerous structures
(Al-Lazikani et al., J. Mol. Biol. 273:927-948 (1997); Morea et
al., Methods 20:267-279 (2000)). Because the number of residues
within a hypervariable region varies in different antibodies,
additional residues relative to the canonical positions are
conventionally numbered with a, b, c and so forth next to the
residue number in the canonical variable domain numbering scheme
(Al-Lazikani et al., supra (1997)). Such nomenclature is similarly
well known to those skilled in the art.
[0081] For example, CDRs defined according to either the Kabat
(hypervariable), Chothia (structural), or MacCallum (J. Mol. Biol.
262:732-745 (1996)) designations, as set forth in the Table 1
below:
TABLE-US-00001 TABLE 1 CDR Definitions Kabat.sup.1 Chothia .sup.2
MacCallum .sup.3 Loop Location V.sub.H CDR1 31-35 26-32 30-35
linking B and C strands V.sub.H CDR2 50-65 53-55 47-58 linking C'
and C'' strands V.sub.H CDR3 95-102 96-101 93-101 linking F and G
strands V.sub.L CDR1 24-34 26-32 30-36 linking B and C strands
V.sub.L CDR2 50-56 50-52 46-55 linking C' and C'' strands V.sub.L
CDR3 89-97 91-96 89-96 linking F and G strands .sup.1Residue
numbering follows the nomenclature of Kabat et al., supra .sup.2
Residue numbering follows the nomenclature of Chothia et al.,
supra
[0082] The term "cancer" refers to any physiological condition in
mammals characterized by unregulated cell growth. Cancers described
herein include solid tumors and hematological (blood) cancers. A
"hematological cancer" refers to any blood borne cancer and
includes, for example, myelomas, lymphomas and leukemias. A "solid
tumor" or "tumor" refers to a lesion and neoplastic cell growth and
proliferation, whether malignant or benign, and all pre-cancerous
and cancerous cells and tissues resulting in abnormal tissue
growth. "Neoplastic," as used herein, refers to any form of
dysregulated or unregulated cell growth, whether malignant or
benign, resulting in abnormal tissue growth.
[0083] The terms "treating" or "treatment" refer to any indicia of
success or amelioration of the progression, severity, and/or
duration of a disease, pathology or condition, including any
objective or subjective parameter such as abatement; remission;
diminishing of symptoms or making the injury, pathology or
condition more tolerable to the patient; slowing in the rate of
degeneration or decline; making the final point of degeneration
less debilitating; or improving a patient's physical or mental
well-being.
[0084] The term "enhance" refers to an increase or improvement in
the function or activity of a protein or cell after administration
or contacting with a combination described herein compared to the
protein or cell prior to such administration or contact.
[0085] The term "administering" refers to the act of delivering a
combination or composition described herein into a subject by such
routes as oral, mucosal, topical, suppository, intravenous,
parenteral, intraperitoneal, intramuscular, intralesional,
intrathecal, intranasal or subcutaneous administration. Parenteral
administration includes intravenous, intramuscular,
intra-arteriole, intradermal, subcutaneous, intraperitoneal,
intraventricular, and intracranial administration. Administration
generally occurs after the onset of the disease, disorder, or
condition, or its symptoms but, in certain instances, can occur
before the onset of the disease, disorder, or condition, or its
symptoms (e.g., administration for patients prone to such a
disease, disorder, or condition).
[0086] The term "coadministration" refers to administration of two
or more agents (e.g., a combination described herein and another
active agent such as an anti-cancer agent described herein). The
timing of coadministration depends in part of the combination and
compositions administered and can include administration at the
same time, just prior to, or just after the administration of one
or more additional therapies, for example cancer therapies such as
chemotherapy, hormonal therapy, radiotherapy, or immunotherapy. The
compound of the invention can be administered alone or can be
coadministered to the patient. Coadministration is meant to include
simultaneous or sequential administration of the compound
individually or in combination (more than one compound or agent).
Thus, the preparations can also be combined, when desired, with
other active substances (e.g., to reduce metabolic degradation).
The compounds described herein can be used in combination with one
another, with other active agents known to be useful in treating
cancer.
[0087] The term "anti-cancer agent" is used in accordance with its
plain ordinary meaning and refers to a composition having
anti-neoplastic properties or the ability to inhibit the growth or
proliferation of cells. In embodiments, an anti-cancer agent is a
chemotherapeutic. In embodiments, an anti-cancer agent is an agent
identified herein having utility in methods of treating cancer. In
embodiments, an anti-cancer agent is an agent approved by the FDA
or similar regulatory agency of a country other than the USA, for
treating cancer.
[0088] The term "chemotherapeutic" or "chemotherapeutic agent" is
used in accordance with its plain ordinary meaning and refers to a
chemical composition or compound having anti-neoplastic properties
or the ability to inhibit the growth or proliferation of cells.
"Chemotherapy" refers to a therapy or regimen that includes
administration of a chemotherapeutic or anti-cancer agent described
herein.
[0089] The terms "halo," "halogen," and "halide" refer to --F,
--Cl, --Br, and --I.
[0090] The term "alkyl" by itself or as part of another substituent
refers to, unless otherwise stated, a straight (e.g., unbranched)
or branched carbon chain (or carbon), or combination thereof,
having no unsaturation and can include mono-, di- and multivalent
radicals. An alkyl as defined herein can be designated by its
number of carbon atoms (e.g., C.sub.1-C.sub.10 means one to ten
carbons). Alkyls herein can include C.sub.1-C.sub.10,
C.sub.1-C.sub.8, C.sub.1-C.sub.6, and C.sub.1-C.sub.4 lengths. A
"perfluoroalkyl" refers to an alkyl in which all of the hydrogens
in the alkyl chain are replaced with fluoro.
[0091] The term "alkoxy" refers to an alkyl group (e.g.,
C.sub.1-C.sub.10, C.sub.1-C.sub.8, C.sub.1-C.sub.6, and
C.sub.1-C.sub.4 alkyl) attached to the remainder of the molecule
via an oxygen linker (--O--). Exemplary alkoxy groups include
groups having the formula --OR, where R is branched or linear
alkyl. A "perfluoroalkoxyl" moiety refers to an alkoxy in which all
of the hydrogens in the alkyl chain are replaced with fluoro.
[0092] The term "aminoalkyl" refers to an alkyl group (e.g.,
C.sub.1-C.sub.10, C.sub.1-C.sub.8, C.sub.1-C.sub.6, and
C.sub.1-C.sub.4 alkyl) in which one or more hydrogen atoms are
replaced with an amino group
[0093] The term "alkylamino" refers to an alkyl group (e.g.,
C.sub.1-C.sub.10, C.sub.1-C.sub.8, C.sub.1-C.sub.6, and
C.sub.1-C.sub.4 alkyl) attached to the remainder of the molecule
via a nitrogen linker (--NR--). Exemplary alkylamino groups include
N-methylamino, N-ethylamino, N-isopropylamino, and the like.
[0094] The term "acyl" refers to a moiety having the formula,
--C(O)R, where R is a substituted or unsubstituted alkyl,
haloalkyl, or amino group. The term "acylamino" refers to an acyl
moiety having an attached amino group and includes, for example,
such moieties as acetylamino, propionylamino, butyrylamino,
isobuytrylamino, and others.
[0095] The term "alkythio" refers to an alkyl group (e.g.,
C.sub.1-C.sub.10, C.sub.1-C.sub.8, C.sub.1-C.sub.6, and
C.sub.1-C.sub.4 alkyl) attached to the remainder of the molecule
via a sulfur linker (--S--). Exemplary alkylthio groups include
methylthio, ethylthio, propylthio, and others.
[0096] The term "heterocycle" or "heterocyclyl" refers to a stable
3- to 15-membered monocyclic group that is saturated or unsaturated
and contains one or more heteroatoms (e.g., N, O, or S). Exemplary
heterocycles include, but are not limited to morpholinyl,
piperidinyl, piperazinyl, pyranyl, pyrrolidinyl, pyrrolinyl,
imidazolidinyl, imidazolinyl, oxetanyl, azetidinyl, and others.
[0097] 1. Compositions
[0098] Provided herein are combinations (e.g., combination
therapies and compositions) useful for treating a variety of
diseases, disorders, and symptoms thereof, including for example,
cancer. The combinations described herein include an HDAC inhibitor
and a PD-L1 inhibitor and/or PD-1 inhibitor, and further a CTLA-4
inhibitor. In one non-limiting example a benzamide HDAC inhibitor
of formula I is provided, and examples of PD-L1 inhibitors, PD-1
inhibitors, and CTLA-4 inhibitors are described herein. In one
aspect is a combination that includes a therapeutically effective
amount of a PD-L1 inhibitor and/or PD-1 inhibitor, a CTLA-4
inhibitor, and a therapeutically effective amount of a compound of
formula I:
##STR00006##
wherein:
[0099] A is a phenyl or heterocyclic group, optionally substituted
with 1 to 4 substituents selected from the group consisting of
halogen, --OH, --NH.sub.2, --NO.sub.2, --CN, --COOH,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
aminoalkyl, C.sub.1-C.sub.4 alkylamino, C.sub.2-C.sub.4 acyl,
C.sub.2-C.sub.4 acylamino, C.sub.1-C.sub.4 alkythio,
C.sub.1-C.sub.4 perfluoroalkyl, C.sub.1-C.sub.4 perfluoroalkyloxy,
C.sub.1-C.sub.4 alkoxycarbonyl, phenyl, and a heterocyclic
group;
[0100] B is phenyl optionally substituted with 1 to 3 substituents
selected from the group consisting of halogen, --OH, --NH.sub.2,
--NO.sub.2, --CN, --COOH, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 aminoalkyl, C.sub.1-C.sub.4 alkylamino,
C.sub.2-C.sub.4 acyl, C.sub.2-C.sub.4 acylamino, C.sub.1-C.sub.4
alkylthio, C.sub.1-C.sub.4 perfluoroalkyl, C.sub.1-C.sub.4
perfluoroalkyloxy, C.sub.1-C.sub.4 alkoxycarbonyl, and phenyl;
[0101] Y is a moiety comprising --CO-- which is linear and in which
the distances between the centroid of ring B (W1), the centroid of
ring A (W2) and an oxygen atom as a hydrogen bond acceptor in the
moiety Y (W3) are: W1-W2=about 6.0 .ANG., W1-W3=about 3.0 .ANG. to
about 6.0 .ANG., and W2-W3=about 4.0 .ANG. to about 8.0 .ANG.,
respectively;
[0102] Z is a bond or C.sub.1-C.sub.4 alkylene, --O--, --S--,
--NH--, --CO--, --CS--, --SO--, or --SO.sub.2--;
[0103] R.sup.1 and R.sup.2 are independently hydrogen or
C.sub.1-C.sub.4 alkyl;
[0104] R.sup.3 is hydrogen or C.sub.1-C.sub.4 alkyl;
[0105] R.sup.4 is hydrogen or --NH.sub.2; and
[0106] one of X.sup.1, X.sup.2, X.sup.3, or X.sup.4 is halogen,
--OH, --NH.sub.2, --NO.sub.2, --CN, --COOH, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 aminoalkyl, C.sub.1-C.sub.4
alkylamino, C.sub.2-C.sub.4 acyl, C.sub.2-C.sub.4 acylamino,
C.sub.1-C.sub.4 alkylthio, C.sub.1-C.sub.4 perfluoroalkyl,
C.sub.1-C.sub.4 perfluoroalkyloxy, or C.sub.1-C.sub.4
alkoxycarbonyl optionally substituted with halogen or
C.sub.1-C.sub.4 alkyl, while the others of X.sup.1, X.sup.2,
X.sup.3, or X.sup.4 are independently hydrogen,
[0107] provided that when R.sup.4 is hydrogen, one of X.sup.1,
X.sup.2, X.sup.3, or X.sup.4 is --NH.sub.2, an aminoalkyl group or
an alkylamino group.
[0108] In certain instances A is phenyl or phenyl optionally
substituted with halogen, --OH, --NH.sub.2, --NO.sub.2, --CN,
--COOH, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 aminoalkyl, C.sub.1-C.sub.4 alkylamino,
C.sub.2-C.sub.4 acyl, C.sub.2-C.sub.4 acylamino, C.sub.1-C.sub.4
alkythio, C.sub.1-C.sub.4 perfluoroalkyl, C.sub.1-C.sub.4
perfluoroalkyloxy, C.sub.1-C.sub.4 alkoxycarbonyl, phenyl, or a
heterocyclic group. A can be a heterocyclic group (e.g., a 5 to
10-membered heterocyclic group) containing a --N--, --S--, or --O--
moiety. In certain instances A is a 5 to 10-membered N-heterocyclic
moiety having 1, 2, 3, 4, or more nitrogen heteroatoms, such as for
example, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imdazolyl,
pyrazolidinyl, pyrazolyl, oxazolidinyl, oxazolyl, thiazolidinyl,
thiazolyl, piperidinyl, pyridinyl, piperizinyl, diazinyl,
tetrazolyl, triazinyl, tetrazinyl, azepinyl, diazepinyl, azocanyl,
or azocinyl. A can be a saturated or unsaturated 5 to 10 membered
N-heterocyclic moiety. In certain instances A is a 6-membered
N-heterocyclic moiety, such as for example, pyridine.
[0109] In certain embodiments, B is phenyl. B can be phenyl
optionally substituted with a small moiety such as, for example,
halogen, --OH, --NH.sub.2, --NO.sub.2, --CN, --COOH, or
C.sub.1-C.sub.4 alkyl. In some embodiments B is phenyl substituted
with halogen. In other embodiments, B is substituted with an
electron donating group (EDG). In still other embodiments, B is
phenyl substituted with an electron withdrawing group (EWG). In yet
another embodiment, B is phenyl substituted with C.sub.1-C.sub.4
alkyl. B can be methyl-, ethyl-, or propyl-substituted phenyl. B
can be methoxy-, ethoxy-, or propoxy-substituted phenyl.
[0110] In certain instances Y is --C(O)NH--CH.sub.2--. In certain
embodiments, Z is a bond. Z can be a methylene, ethylene, or
propylene moiety. In some embodiments, Z is --O--, --S--, --NH--,
--CO--, --CS--, --SO--, or --SO.sub.2--.
[0111] R.sup.1 and R.sup.2 are in certain instances both hydrogen.
R.sup.1 and R.sup.2 can both be C.sub.1-C.sub.4 alkyl, for example,
R.sup.1 and R.sup.2 can both be methyl, ethyl, or propyl. In
certain instances if one of R.sup.1 or R.sup.2 is hydrogen the
other is C.sub.1-C.sub.4 alkyl (e.g., methyl). R.sup.3 can be
hydrogen. In other embodiments, R.sup.3 is C.sub.1-C.sub.4 alkyl
(e.g., methyl or ethyl).
[0112] R.sup.4 can be --NH.sub.2. In certain instances R.sup.4 is
--NH.sub.2 where one of X.sup.1, X.sup.2, X.sup.3, or X.sup.4 is
halogen. When R.sup.4 is --NH.sub.2, X.sup.2 or X.sup.3 can be
halogen. In one embodiment R.sup.4 is --NH.sub.2 and X.sup.2 is
halogen. In such instances X.sup.2 can be --F.
[0113] In another embodiment, R.sup.1, R.sup.2, and R.sup.3 are
hydrogen where Z is a bond, R.sup.4 is --NH.sub.2 and Y is
--C(O)NH--CH.sub.2--. In such embodiments, A can be a heterocyclic
moiety as described above and B can be phenyl. X.sup.1, X.sup.2,
X.sup.3, or X.sup.4 can be halogen (e.g., --F) or --NH.sub.2.
[0114] The compound of formula I can be a compound as substantially
described by U.S. Pat. Nos. 7,244,751 and 7,550,490 both of which
are incorporated herein by reference in their entirety for all
purposes. In one embodiment the compound of formula I is
N-(2-amino-4-fluorophenyl)-4-[[[(2E)-1-oxo-3-(3-pyridinyl)-2-propen-1-yl]-
amino]methyl]benzamide. In another embodiment the compound of
formula I has the formula Ia as set forth below:
##STR00007##
[0115] Compounds of formula I as described herein include
pharmaceutically acceptable salts, pharmaceutically acceptable
stereoisomers, prodrugs, enantiomers, diastereomers, hydrates,
co-crystals, and polymorphs thereof.
[0116] In certain instances, the combination includes a compound of
formula I (e.g., Ia) present at an amount of greater than about: 1
mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35
mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg,
125 mg, 150 mg, 175 mg, or 200 mg. The combination can include a
compound of formula I present at an amount greater than about: 1
mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg. In
certain instances the compound of formula I is present in an amount
greater than about 5 mg or about 10 mg. The combination can include
a compound of formula I present at an amount greater than about: 1
mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg
to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to
about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, or 100 mg
to about 200 mg.
[0117] The combination can include a compound present in an amount
of at least about: 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20
mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg,
85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg. The
combination can include a compound of formula I present at an
amount of at least about: 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg,
8 mg, 9 mg, or 10 mg. In certain instances the compound of formula
I is present in an amount of at least about 5 mg or about 10 mg.
The combination can include a compound of formula I present at an
amount of at least about: 1 mg to about 10 mg, 1 mg to about 25 mg,
1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg
to about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg
to about 100 mg, or 100 mg to about 200 mg.
[0118] The combination can include a compound present in an amount
of about: 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg,
30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90
mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg. The combination can
include a compound of formula I present at an amount of about: 1
mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, or 10 mg. In
certain instances the compound of formula I is present in an amount
of about 5 mg or about 10 mg. The combination can include a
compound of formula I present at an amount of about: 1 mg to about
10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg to about 10
mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg,
10 mg to about 50 mg, 50 mg to about 100 mg, or 100 mg to about 200
mg.
[0119] A compound of formula I can be present in the combinations
described herein relative to the weight of the patient (e.g.,
mg/kg). In some instances, the compound of formula I is present in
an amount equivalent to about: 0.0001 mg/kg to about 200 mg/kg,
0.001 mg/kg to about 200 mg/kg, 0.01 mg/kg to about 200 mg/kg, 0.01
mg/kg to about 150 mg/kg, 0.01 mg/kg to about 100 mg/kg, 0.01 mg/kg
to about 50 mg/kg, 0.01 mg/kg to about 25 mg/kg, 0.01 mg/kg to
about 10 mg/kg, or 0.01 mg/kg to about 5 mg/kg, 0.05 mg/kg to about
200 mg/kg, 0.05 mg/kg to about 150 mg/kg, 0.05 mg/kg to about 100
mg/kg, 0.05 mg/kg to about 50 mg/kg, 0.05 mg/kg to about 25 mg/kg,
0.05 mg/kg to about 10 mg/kg, or 0.05 mg/kg to about 5 mg/kg, 0.5
mg/kg to about 200 mg/kg, 0.5 mg/kg to about 150 mg/kg, 0.5 mg/kg
to about 100 mg/kg, 0.5 mg/kg to about 50 mg/kg, 0.5 mg/kg to about
25 mg/kg, 0.5 mg/kg to about 10 mg/kg, or 0.5 mg/kg to about 5
mg/kg. In other instances the compound of formula I is present in
an amount equivalent to about: 1 mg/kg to about 200 mg/kg, 1 mg/kg
to about 150 mg/kg, 1 mg/kg to about 100 mg/kg, 1 mg/kg to about 50
mg/kg, 1 mg/kg to about 25 mg/kg, 1 mg/kg to about 10 mg/kg, or 1
mg/kg to about 5 mg/kg.
PD-L1 Inhibitors
[0120] PD-L1 inhibitors useful in the combinations described herein
include any molecule capable of inhibiting, blocking, abrogating or
interfering with the binding of PD-L1 to PD-1, activity or
expression of PD-L1. In particular, a PD-L1 inhibitor can be a
small molecule compound, a nucleic acid, a polypeptide, an
antibody, a peptibody, a diabody, a minibody, a single-chain
variable fragment (ScFv), or a functional fragment or variant
thereof. In one instance the PD-L1 inhibitor is a small molecule
compound (e.g., a compound having a molecule weight of less than
about 1000 Da). In one embodiment, the PD-L1 inhibitor is CA-170
(AUPM-170; Curis, Inc.), In other instances, useful PD-L1
inhibitors in the combinations described herein include nucleic
acids and polypeptides. The PD-L1 inhibitor can be a polypeptide
(e.g., macrocyclic polypeptide) such as those exemplified in U.S.
Patent Application Publication No.: 2014/0294898, which is
incorporated herein by reference in its entirety and for all
purposes. In one example, the PD-L1 inhibitor is an antibody,
peptibody, diabody, minibody, ScFv, or a functional fragment
thereof. In another example, the PD-L1 inhibitor is a PD-L1
inhibitor antibody. The PD-L1 inhibitor antibody can be a
monoclonal or polyclonal antibody. In certain embodiments, the
PD-L1 inhibitor antibody is a monoclonal antibody.
[0121] PD-L1 antibodies include all known types of antibodies and
functional fragments thereof, including but not limited to, those
exemplified herein such as, for example, human antibodies, mouse
antibodies, chimeric antibodies, humanized antibodies, or chimeric
humanized antibodies.
[0122] In one embodiment, the PD-L1 inhibitor antibody is a human
antibody. In another embodiment, the PD-L1 inhibitor antibody is a
mouse antibody. In still another embodiment, the PD-L1 inhibitor
antibody is a chimeric antibody. In yet another embodiment, the
PD-L1 inhibitor antibody is a humanized antibody. In yet another
embodiment, the PD-L1 inhibitor antibody is a chimeric humanized
antibody. The PD-L1 inhibitor antibody can be a human antibody or
humanized antibody. The PD-L1 inhibitor antibody can be durvalumab,
avelumab, atezolizumab, BMS-936559, STI-A1010, STI-A1011,
STI-A1012, STI-A1013, STI-A1014, or STI-A1015. In some embodiments,
two or more PD-L1 antibodies are administered in combination with a
compound of formula I as described herein.
[0123] The PD-L1 inhibitor antibody can be durvalumab. Durvalumab
is an Fc optimized monoclonal antibody directed against PD-L1, with
potential immune checkpoint inhibitory and anti-neoplastic
activities. Without being bound by any particular theory,
durvalumab binds to PD-L1, thereby blocking its binding to and
activation of its receptor, PD-1, which can be expressed on
activated T-cells. This can reverse T-cell inactivation and
activate the immune system to exert a cytotoxic T-lymphocyte (CTL)
response against PD-L1-expressing tumor cells. The Fc region of
durvalumab is modified in such a way that it does not induce either
antibody-dependent cytotoxicity (ADCC) or complement-dependent
cytotoxicity (CDC).
[0124] The PD-L1 inhibitor antibody can be avelumab. Avelumab is a
human immunoglobulin G1 (IgG1) monoclonal antibody directed against
PD-L1, with potential immune checkpoint inhibitory and
anti-neoplastic activities. Without being bound by any particular
theory, avelumab binds to PD-L1 and prevents the interaction of
PD-L1 with its receptor, PD-1. This inhibits the activation of PD-1
and its downstream signaling pathways. This can restore immune
function through the activation of cytotoxic T-lymphocytes (CTLs)
targeted to PD-L1-overexpressing tumor cells. Avelumab appears to
induce an antibody-dependent cellular cytotoxic (ADCC) response
against PD-L1-expressing tumor cells.
[0125] The PD-L1 inhibitor antibody can be atezolizumab.
Atezolizumab is a human, Fc optimized, monoclonal antibody directed
against the protein ligand PD-L1, with potential immune checkpoint
inhibitory and anti-neoplastic activities. Without being bound by
any particular theory, atezolizumab binds to PD-L1, blocking its
binding to and activation of its receptor, PD-1, expressed on
activated T-cells, which may enhance the T-cell-mediated immune
response to neoplasms and reverse T-cell inactivation. In addition,
by binding to PD-L1, atezolizumab also appears to prevent binding
of PD-L1 to B7.1 expressed on activated T cells, which can further
enhance the T-cell-mediated immune response. The Fc region of
atezolizumab is modified in such a way that it does not induce
either antibody-dependent cytotoxicity (ADCC) or
complement-dependent cytotoxicity (CDC).
[0126] The PD-L1 inhibitor antibody can be BMS-936559. BMS-936559
is a fully human IgG4 monoclonal antibody directed against PD-L1,
with potential immune checkpoint inhibitory activity. Without being
bound by any particular theory, BMS-936559 binds to PD-L1 and
inhibits its binding to both PD-1 and CD80.
[0127] The PD-L1 inhibitor antibody can be STI-A1010, STI-A1011,
STI-A1012, STI-A1013, STI-A1014, or STI-A1015. STI-A1010,
STI-A1011, STI-A1012, STI-A1013, STI-A1014, and STI-A1015 (Sorrento
Therapeutics) are fully human monoclonal antibodies that are each
directed against PD-L1.
PD-1 Inhibitors
[0128] PD-1 inhibitors useful in the combinations described herein
include any molecule capable of inhibiting, blocking, abrogating or
interfering with the activity or expression of PD-1. In particular,
a PD-1 inhibitor can be a small molecule compound, a nucleic acid,
a polypeptide, an antibody, a peptibody, a diabody, a minibody, a
single-chain variable fragment (ScFv), or a functional fragment or
variant thereof. In one instance the PD-1 inhibitor is a small
molecule compound (e.g., a compound having a molecule weight of
less than about 1000 Da.) In other instances, useful PD-1
inhibitors in the combinations described herein include nucleic
acids and polypeptides. The PD-1 inhibitor can be a polypeptide
(e.g., macrocyclic polypeptide) such as those exemplified in U.S.
Patent Application Publication No.: 2014/0294898, which is
incorporated herein by reference in its entirety and for all
purposes. In one example, the PD-1 inhibitor is an antibody,
peptibody, diabody, minibody, ScFv, or a functional fragment
thereof. In one example, the PD-1 inhibitor is AMP-224 (GSK).
[0129] AMP-224 is a recombinant fusion protein comprising an
extracellular domain of the PD-1 ligand programmed cell death
ligand 2 (PD-L2) and an Fc region of human IgG. Certain cancers can
evade and suppress the immune system, in part, and without being
bound by any particular theory by interactions between PD-1 and
B7-H1. AMP-224 appears to block this interaction and therefore
appears to overcome immune suppression.
[0130] In another example, the PD-1 inhibitor is a PD-1 antibody.
The PD-1 antibody can be a monoclonal or polyclonal antibody. In
certain embodiments, the PD-1 antibody is a monoclonal
antibody.
[0131] PD-1 antibodies include all known types of antibodies and
functional fragments thereof, including but not limited to, those
exemplified herein such as, for example, human antibodies, mouse
antibodies, chimeric antibodies, humanized antibodies, or chimeric
humanized antibodies.
[0132] In one embodiment, the PD-1 antibody is a human antibody. In
another embodiment, the PD-1 antibody is a mouse antibody. In still
another embodiment, the PD-1 antibody is a chimeric antibody. In
yet another embodiment, the PD-1 antibody is a humanized antibody.
In yet another embodiment, the PD-1 antibody is a chimeric
humanized antibody. The PD-1 antibody can be a human antibody or
humanized antibody. The PD-1 antibody can be nivolumab,
pembrolizumab, pidilizumab, REGN2810, PDR 001, or MEDI0680. In some
embodiments, two or more PD-1 antibodies are administered in
combination with a compound of formula I as described herein.
[0133] The PD-1 antibody can be nivolumab. Nivolumab (marketed as
OPDIVO) is a fully human monoclonal antibody directed against PD-1
with immunopotentiation activity. Without being bound by any
particular theory, nivolumab binds to and blocks the activation of
PD-1 by its cognate ligands, resulting in the activation of T-cells
and cell-mediated immune responses against tumor cells or
pathogens.
[0134] The PD-1 antibody can be pembrolizumab. Pembrolizumab
(MK-3475, marketed as KEYTRUDA) is a humanized monoclonal IgG4
antibody directed against human cell surface receptor PD-1 with
potential immunopotentiating activity. Without being bound by any
particular theory, pembrolizumab binds to PD-1, an inhibitory
signaling receptor expressed on the surface of activated T cells,
and blocks the binding to and activation of PD-1 by its cognate
ligands. The blocking of binding and activity results in the
activation of T-cell-mediated immune responses against tumor
cells.
[0135] The PD-1 antibody can be pidilizumab. Pidilizumab (CT-011)
is a humanized monoclonal antibody directed against human PD-1 with
immunomodulating and antitumor activities. Without being bound by
any particular theory, pidilizumab blocks interaction between the
receptor PD-1 with its ligands, resulting in the attenuation of
apoptotic processes in lymphocytes, primarily effector/memory T
cells, and the augmentation of the anti-tumor activities of NK
cells.
[0136] The PD-1 antibody can be REGN2810. REGN2810 is a human
monoclonal antibody directed against PD-1, with potential immune
checkpoint inhibitory and anti-neoplastic activity. Without being
bound by any particular theory REGN2810 binds to PD-1, inhibits
binding to its cognate ligand, and prevents the activation of its
downstream signaling pathways. This can restore immune function
through the activation of cytotoxic T-cells.
[0137] The PD-1 antibody can be PDR 001. PDR 001 is a fully
humanized monoclonal antibody directed against PD-1, with immune
checkpoint inhibitory and anti-neoplastic activities. Without being
bound by any particular theory, PDR 001 binds to PD-1 expressed on
activated T-cells and blocks the interaction with its cognate
ligands. The inhibition of ligand binding prevents PD-1-mediated
signaling and results in both T-cell activation and the induction
of T-cell-mediated immune responses against tumor cells.
[0138] The PD-1 antibody can be MEDI0680 (AMP-514) is a monoclonal
antibody directed against the PD-1, with potential immunomodulating
and anti-neoplastic activity. Without being bound by any particular
theory, MEDI0680 appears to inhibit the activation of PD-1 and its
downstream signaling pathways. This inhibition can restore immune
function through the activation both of T-cells and cell-mediated
immune responses against PD-1 overexpressing tumor cells.
CTLA-4 Inhibitors
[0139] CTLA-4 inhibitors useful in the combinations described
herein include any molecule capable of inhibiting, blocking,
abrogating or interfering with the activity or expression of
CTLA-4. In particular, a CTLA-4 inhibitor can be a small molecule
compound, a nucleic acid, a polypeptide, an antibody, a peptibody,
a diabody, a minibody, a single-chain variable fragment (ScFv), or
a functional fragment or variant thereof. In one instance the
CTLA-4 inhibitor is a small molecule compound (e.g., a compound
having a molecule weight of less than about 1000 Da.) In other
instances, useful CTLA-4 inhibitors in the combinations described
herein include nucleic acids and polypeptides. The CTLA-4 inhibitor
can be a polypeptide (e.g., macrocyclic polypeptide). In one
example, the CTLA-4 inhibitor is an antibody, peptibody, diabody,
minibody, ScFv, or a functional fragment thereof. In one example,
the CTLA-4 inhibitor is ipilimumab.
[0140] In another example, the CTLA-4 inhibitor is a CTLA-4
antibody. The CTLA-4 antibody can be a monoclonal or polyclonal
antibody. In certain embodiments, the CTLA-4 antibody is a
monoclonal antibody.
[0141] CTLA-4 antibodies include all known types of antibodies and
functional fragments thereof, including but not limited to, those
exemplified herein such as, for example, human antibodies, mouse
antibodies, chimeric antibodies, humanized antibodies, or chimeric
humanized antibodies. In one embodiment, the CTLA-4 antibody is a
human antibody. In another embodiment, the CTLA-4 antibody is a
mouse antibody. In still another embodiment, the CTLA-4 antibody is
a chimeric antibody. In yet another embodiment, the CTLA-4 antibody
is a humanized antibody. In yet another embodiment, the CTLA-4
antibody is a chimeric humanized antibody. The CTLA-4 antibody can
be a human antibody or humanized antibody. The CTLA-4 antibody can
be administered in combination with a compound of formula I as
described herein.
CD276 Inhibitors
[0142] CD276 (B7-H3) is a relatively newly discovered, but
important member of the immune checkpoint family. CD276 is
expressed on antigen-presenting cells in active/inflamed "hot"
tumor micro-environments ("TMEs") and suppresses CD8.sup.+
cytotoxic T cells. CD276 expression is upregulated with
administration of a compound of formula I as described herein.
CD276 inhibitors useful in the combinations described herein
include any molecule capable of inhibiting, blocking, abrogating or
interfering with the activity or expression of CD276. In
particular, a CD276 inhibitor can be a small molecule compound, a
nucleic acid, a polypeptide, an antibody, a peptibody, a diabody, a
minibody, a single-chain variable fragment (ScFv), or a functional
fragment or variant thereof. In one instance the CD276 inhibitor is
a small molecule compound (e.g., a compound having a molecule
weight of less than about 1000 Da.) In other instances, useful
CD276 inhibitors in the combinations described herein include
nucleic acids and polypeptides. The CD276 inhibitor can be a
polypeptide (e.g., macrocyclic polypeptide). In one example, the
CD276 inhibitor is an antibody, peptibody, diabody, minibody, ScFv,
or a functional fragment thereof.
[0143] In another example, the CD276 inhibitor is a CD276 antibody.
The CD276 antibody can be a monoclonal or polyclonal antibody. In
certain embodiments, the CD276 antibody is a monoclonal
antibody.
[0144] CD276 antibodies include all known types of antibodies and
functional fragments thereof, including but not limited to, those
exemplified herein such as, for example, human antibodies, mouse
antibodies, chimeric antibodies, humanized antibodies, or chimeric
humanized antibodies.
[0145] In one embodiment, the CD276 antibody is a human antibody.
In another embodiment, the CD276 antibody is a mouse antibody. In
still another embodiment, the CD276 antibody is a chimeric
antibody. In yet another embodiment, the CD276 antibody is a
humanized antibody. In yet another embodiment, the CD276 antibody
is a chimeric humanized antibody. The CD276 antibody can be a human
antibody or humanized antibody. The CD276 antibody can be
administered in combination with a compound of formula I as
described herein, or with any of the other compositions described
herein.
[0146] A PD-L1 inhibitor antibody, PD-1 inhibitor antibody, CTLA-4
inhibitor antibody, and/or CD276 inhibitor antibody (any one of
which is referred to as "Inhibitor Antibody" herein) can be of any
antibody isotype. The term isotype refers to the antibody class
that is encoded by heavy chain constant region genes. The heavy
chains of a given antibody or functional fragment determine the
class of that antibody or functional fragment: IgM, IgG, IgA, IgD
or IgE. Each class can have either .kappa. or .lamda.. light
chains. The term subclass refers to the minor differences in amino
acid sequences of the heavy chains that differentiate the
subclasses. In humans there are two subclasses of IgA (subclasses
IgA1 and IgA2) and there are four subclasses of IgG (subclasses
IgG1, IgG2, IgG3 and IgG4). Such classes and subclasses are well
known to those skilled in art.
[0147] Useful Inhibitor Antibodies bind to their substrates with
sufficient strength to inhibit activity of the substrate (e.g.,
PD-L1, PD-1, CTLA-4, and/or CD276). The term bind as used herein
refers to an interaction between molecules to form a complex.
Interactions can be, for example, non-covalent interactions
including hydrogen bonds, ionic bonds, hydrophobic interactions,
and/or van der Waals interactions. A complex can also include the
binding of two or more molecules held together by covalent or
non-covalent bonds, interactions or forces. Binding of an antibody
or functional fragment thereof can be detected using, for example,
an enzyme-linked immunosorbant assay or any one of a number of
methods that are well known to those skilled in the art.
[0148] The strength of the total non-covalent interactions between
a single antigen-binding site on an Inhibitor Antibody or
functional fragment and a single epitope of a target molecule is
the affinity of the antibody or functional fragment for that
epitope. The ratio of association (k.sub.1) to dissociation
(k.sub.1) of an antibody or functional fragment thereof to a
monovalent antigen (k.sub.1/k.sub.1) is the association constant K,
which is a measure of affinity. The value of K varies for different
complexes of antibody or functional fragment and antigen and
depends on both k.sub.1 and k.sub.-1. The association constant K
for an antibody or functional fragment of the invention can be
determined using any method provided herein or any other method
well known to those skilled in the art.
[0149] The affinity at one binding site does not always reflect the
true strength of the interaction between an antibody or functional
fragment and an antigen. When complex antigens containing multiple,
repeating antigenic determinants come in contact with antibodies
containing multiple binding sites, the interaction of such an
antibody or functional fragment with antigen at one site will
increase the probability of a reaction at a second site. The
strength of such multiple interactions between a multivalent
antibody and antigen is called the avidity. The avidity of an
antibody or functional fragment can be a better measure of its
binding capacity than is the affinity of its individual binding
sites. For example, high avidity can compensate for low affinity as
is sometimes found for pentameric IgM antibodies, which can have a
lower affinity than IgG, but the high avidity of IgM, resulting
from its multivalence, enables it to bind antigen effectively.
[0150] The specificity of an Inhibitor Antibody or functional
fragment thereof refers to the ability of an individual antibody or
functional fragment thereof to react with only one antigen (e.g., a
single epitope of PD-L1, PD-1, and CTLA-4). An antibody or
functional fragment can be considered specific when it can
distinguish differences in the primary, secondary or tertiary
structure of an antigen or isomeric forms of an antigen.
[0151] The Inhibitor Antibody can be present in an amount as a
measure with regards to the weight of the patient in need thereof.
For example, the Inhibitor Antibody can be present in an amount of
about: 0.1 mg/kg to about 50 mg/kg, 0.1 mg/kg to about 40 mg/kg,
0.1 mg/kg to about 30 mg/kg, 0.1 mg/kg to about 25 mg/kg, 0.1 mg/kg
to about 20 mg/kg, 0.1 mg/kg to about 15 mg/kg, 0.1 mg/kg to about
10 mg/kg, 0.1 mg/kg to about 7.5 mg/kg, 0.1 mg/kg to about 5 mg/kg,
0.1 mg/kg to about 2.5 mg/kg, or about 0.1 mg/kg to about 1 mg/kg.
The Inhibitor Antibody can be present in an amount of about: 0.5
mg/kg to about 50 mg/kg, 0.5 mg/kg to about 40 mg/kg, 0.5 mg/kg to
about 30 mg/kg, 0.5 mg/kg to about 25 mg/kg, 0.5 mg/kg to about 20
mg/kg, 0.5 mg/kg to about 15 mg/kg, 0.5 mg/kg to about 10 mg/kg,
0.5 mg/kg to about 7.5 mg/kg, 0.5 mg/kg to about 5 mg/kg, 0.5 mg/kg
to about 2.5 mg/kg, or about 0.5 mg/kg to about 1 mg/kg. The
Inhibitor Antibody can be present in an amount of about 0.5 mg/kg
to about 5 mg/kg or about 0.1 mg/kg to about 10 mg/kg. The
Inhibitor Antibody can be present in an amount of about 0.1 mg/kg
to about 20 mg/kg or about 0.1 mg/kg to about 30 mg/kg.
[0152] In still other embodiments, the Inhibitor Antibody can be
present at an amount of about: 0.1 mg/kg, 0.5 mg/kg, 1 mg/kg, 2
mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25
mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, or 50 mg/kg. The Inhibitor
Antibody can be present at an amount of about: 1 mg/kg, 2 mg/kg, 3
mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, or 30
mg/kg. The Inhibitor Antibody can be present at an amount of about:
3 mg/kg, 10 mg/kg, 20 mg/kg, or 30 mg/kg.
[0153] The Inhibitor Antibody can be present in the combination at
an amount of about: 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg,
40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 150 mg, or
200 mg. The Inhibitor Antibody can be present in the combination at
an amount of about: 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg,
800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500
mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, or 2000 mg. The Inhibitor
Antibody can be present in the combination at an amount of about
1000 mg to about 2000 mg. The Inhibitor Antibody can be present in
the combination at an amount of about: 1 mg to about 10 mg, 10 mg
to about 20 mg, 25 mg to about 50 mg, 30 mg to about 60 mg, 40 mg
to about 50 mg, 50 mg to about 100 mg, 75 mg to about 150 mg, 100
mg to about 200 mg, 200 mg to about 500 mg, 500 mg to about 1000
mg, 1000 mg to about 1200 mg, 1000 mg to about 1500 mg, 1200 mg to
about 1500 mg, or 1500 to about 2000 mg.
[0154] The Inhibitor Antibody can be present in the combination in
an amount of about 0.1 mg/mL, 0.5 mg/mL, 1 mg/mL, 2 mg/mL, 3 mg/mL,
4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8 mg/mL, 9 mg/mL, 10 mg/mL, 15
mg/mL, 20 mg/mL, 25 mg/mL, 30 mg/mL, 40 mg/mL, 50 mg/mL, 60 mg/mL,
70 mg/mL, 80 mg/mL, 90 mg/mL, 100 mg/mL, 150 mg/mL, 200 mg/mL, 250
mg/mL, 300 mg/mL, 400 mg/mL, or 500 mg/mL. In one embodiment, the
Inhibitor Antibody is present in the combination in an amount of
about: 1 mg/mL to about 10 mg/mL, 5 mg/mL to about 10 mg/mL, 5
mg/mL to about 15 mg/mL, 10 mg/mL to about 25 mg/mL; 20 mg/mL to
about 30 mg/mL; 25 mg/mL to about 50 mg/mL, or 50 mg/mL to about
100 mg/mL.
[0155] In certain instances the therapeutically effective amount of
an Inhibitor Antibody is determined as an amount provided in a
package insert provided with the Inhibitor Antibody. The term
package insert refers to instructions customarily included in
commercial packages of medicaments approved by the FDA or a similar
regulatory agency of a country other than the USA, which contains
information about, for example, the usage, dosage, administration,
contraindications, and/or warnings concerning the use of such
medicaments.
[0156] Compounds of formula I as described herein can be provided
in amounts that are synergistic with the amount of the PD-L1 and/or
PD-1 inhibitor, and a CTLA-4 inhibitor. The term synergistic refers
to a combination described herein (e.g., a compound of formula I
and a PD-L1 and/or PD-1 inhibitor, plus a CTLA-4
inhibitor--including coadministration with another active agent
such as an anti-cancer agent described herein) or a combination of
regimens such as those described herein that is more effective than
the additive effects of each individual therapy or regimen.
[0157] A synergistic effect of a combination described herein can
permit the use of lower dosages of one or more of the components of
the combination (e.g., a compound of formula I, or a PD-L1
inhibitor, or a PD-1 inhibitor, or a CTLA-4 inhibitor). A
synergistic effect can permit less frequent administration of at
least one of the administered therapies (e.g., a compound of
formula I, or a PD-L1 inhibitor, or a PD-1 inhibitor, or a CTLA-4
inhibitor) to a subject with a disease, disorder, or condition
described herein. Such lower dosages and reduced frequency of
administration can reduce the toxicity associated with the
administration of at least one of the therapies (e.g., a compound
of formula I, or a PD-L1 inhibitor, or a PD-1 inhibitor, or a
CTLA-4 inhibitor) to a subject without reducing the efficacy of the
treatment. A synergistic effect as described herein avoid or reduce
adverse or unwanted side effects associated with the use of any
therapy.
[0158] 2. Pharmaceutical Compositions
[0159] Combinations described herein can be provided as a
pharmaceutical composition suitable for administration via any
route to a patient described herein including but not limited to:
oral, mucosal (e.g., nasal, inhalation, pulmonary, sublingual,
vaginal, buccal, or rectal), parenteral (e.g., subcutaneous,
intravenous, bolus injection, intramuscular, or intra-arterial),
topical (e.g., eye drops or other ophthalmic preparations),
transdermal or transcutaneous administration to a patient.
[0160] Exemplary of dosage forms include: tablets; caplets;
capsules (e.g., gelatin capsules); cachets; lozenges;
suppositories; powders; gels; liquid dosage forms suitable for
parenteral administration to a patient; and sterile solids (e.g.,
crystalline or amorphous solids) that can be reconstituted to
provide liquid dosage forms suitable for parenteral administration
to a patient.
[0161] Pharmaceutical compositions and dosage forms described
herein typically include one or more excipients. Suitable
excipients are well known to those skilled in the art of pharmacy.
Whether a particular excipient is suitable for incorporation into a
pharmaceutical composition or dosage form depends on a variety of
factors such as, for example, the intended route of administration
to the patient. Pharmaceutical compositions described herein can
include other agents such as stabilizers, lubricants, buffers, and
disintegrants that can reduce the rate by which an active
ingredient can decompose in a particular formulation.
[0162] Pharmaceutical compositions described herein can in certain
instances include additional active agents other than those in the
combinations described herein (e.g., an anti-cancer agent such as
those described herein) in an amount provided herein.
[0163] In one embodiment, the compound of formula I is provided in
an oral dosage form such as a tablet or capsule. In another
embodiment, the compound of formula I is supplied as a powder
(e.g., lyophilized powder) that can be resuspended in a liquid
suitable for parenteral administration.
[0164] PD-L1 inhibitors, PD-1 inhibitors, and CTLA-4 inhibitors
described herein can be provided in forms convenient to or
facilitate their administration to a patient. For example, where
the inhibitor is an Inhibitor Antibody as described herein, the
inhibitor can be formulated as a ready to use solution for
parenteral administration. In other examples, the inhibitor,
including for example an Inhibitor Antibody, can be formulated as a
powder (e.g., lyophilized powder) that can be resuspended in a
liquid suitable for parenteral administration. In one embodiment,
the combination includes an Inhibitor Antibody formulated for
intravenous administration. In still another embodiment the
combination includes a compound of formula I formulated as an oral
dosage form (e.g., a tablet or capsule) and an Inhibitor Antibody
formulated for intravenous administration.
[0165] Combinations described herein can be provided as controlled
release pharmaceutical products, which have a goal of improving
drug therapy over that achieved by their non-controlled
counterparts. Controlled release formulations can extend activity
of the drug, reduce dosage frequency, and increase subject
compliance. In addition, controlled release formulations can be
used to affect the time of onset of action or other
characteristics, such as blood levels of the drug, and can thus
affect the occurrence of side (e.g., adverse) effects.
[0166] 3. Kits
[0167] The combinations and pharmaceutical compositions described
herein can be provided as part of a kit. Such kits can, for
example, improve patient compliance or improve the accuracy or ease
of preparation for administering the combination. The kit includes
a compound of formula I where the compound is supplied in a
formulation as described herein.
[0168] Kits of the invention can include the combinations described
herein having the same or different formulation. Each component of
a combination described herein in a kit can be supplied in a
separate, individual container. Alternatively or additionally,
components of the combinations described herein can be supplied in
a single container. In such instances, the container can be a
container that is ready for administration to a patient in need
thereof, such as for example, an IV bag, ampoule, or a syringe. In
one embodiment, the compound of formula I in the kit is formulated
for oral administration (e.g., a tablet, capsule, or sachet).
[0169] The contents of kits described herein can be provided in
sterile form. The kit and its contents can be provided in a form
that is ready for administration to the subject in need. In such
instances, the components of the combination of the kit are
supplied as a formulation and optionally in an administration
device such that administration requires little to no further
action by the user. Where kits include administration devices, such
devices include devices known and understood by those skilled in
the art for routes of administration described herein, such as but
not limited to, syringes, pumps, bags, cups, inhalers, droppers,
patches, creams, or injectors.
[0170] 4. Method
[0171] The combinations, pharmaceutical compositions, and kits
described herein are useful for treating diseases, disorders, or
alleviating or eliminating the symptoms of diseases and disorders
such as, for example, cancer. It is to be understood that the
methods described herein pertain to administration of combinations
and pharmaceutical compositions described herein, and such
combinations and pharmaceutical compositions can be provided in the
form of a kit as described herein. Provided herein are methods of
treating cancer by administering a therapeutically effective amount
of a combination described herein to a patient in need thereof.
Also provided herein are methods of managing cancer by
administering therapeutically effective amount of a combination
described herein to a patient in need thereof.
[0172] In some embodiments, the combination is used to treat
cancer. In some embodiments, the cancer is a cancer described
herein.
[0173] In some embodiments, the combination is an HDAC inhibitor
(HDACi) a PD-L1 inhibitor, and a CTLA-4 inhibitor. In some
embodiments, the combination is an HDAC inhibitor (HDACi) a PD-1
inhibitor, and a CTLA-4 inhibitor.
[0174] Combinations useful in the methods described herein include
a compound of formula I:
##STR00008##
[0175] where:
[0176] A is a phenyl or heterocyclic group, optionally substituted
with 1 to 4 substituents selected from the group consisting of
halogen, --OH, --NH.sub.2, --NO.sub.2, --CN, --COOH,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
aminoalkyl, C.sub.1-C.sub.4 alkylamino, C.sub.2-C.sub.4 acyl,
C.sub.2-C.sub.4 acylamino, C.sub.1-C.sub.4 alkythio,
C.sub.1-C.sub.4 perfluoroalkyl, C.sub.1-C.sub.4 perfluoroalkyloxy,
C.sub.1-C.sub.4 alkoxycarbonyl, phenyl, and a heterocyclic
group;
[0177] B is phenyl optionally substituted with 1 to 3 substituents
selected from the group consisting of halogen, --OH, --NH.sub.2,
--NO.sub.2, --CN, --COOH, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 aminoalkyl, C.sub.1-C.sub.4 alkylamino,
C.sub.2-C.sub.4 acyl, C.sub.2-C.sub.4 acylamino, C.sub.1-C.sub.4
alkylthio, C.sub.1-C.sub.4 perfluoroalkyl, C.sub.1-C.sub.4
perfluoroalkyloxy, C.sub.1-C.sub.4 alkoxycarbonyl, and phenyl;
[0178] Y is a moiety comprising --CO-- which is linear and in which
the distances between the centroid of ring B (W1), the centroid of
ring A (W2) and an oxygen atom as a hydrogen bond acceptor in the
moiety Y (W3) are: W1-W2=about 6.0 .ANG., W1-W3=about 3.0 .ANG. to
about 6.0 .ANG., and W2-W3=about 4.0 .ANG. to about 8.0 .ANG.,
respectively;
[0179] Z is a bond or C.sub.1-C.sub.4 alkylene, --O--, --S--,
--NH--, --CO--, --CS--, --SO--, or --SO.sub.2--;
[0180] R.sup.1 and R.sup.2 are independently hydrogen or
C.sub.1-C.sub.4 alkyl;
[0181] R.sup.3 is hydrogen or C.sub.1-C.sub.4 alkyl;
[0182] R.sup.4 is hydrogen or --NH.sub.2, and
[0183] one of X.sup.1, X.sup.2, X.sup.3, or X.sup.4 is halogen,
--OH, --NH.sub.2, --NO.sub.2, --CN, --COOH, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 aminoalkyl, C.sub.1-C.sub.4
alkylamino, C.sub.2-C.sub.4 acyl, C.sub.2-C.sub.4 acylamino,
C.sub.1-C.sub.4 alkylthio, C.sub.1-C.sub.4 perfluoroalkyl,
C.sub.1-C.sub.4 perfluoroalkyloxy, or C.sub.1-C.sub.4
alkoxycarbonyl optionally substituted with halogen or
C.sub.1-C.sub.4 alkyl, while the others of X.sup.1, X.sup.2,
X.sup.3, or X.sup.4 are independently hydrogen,
[0184] provided that when R.sup.4 is hydrogen, one of X.sup.1,
X.sup.2, X.sup.3, or X.sup.4 is --NH.sub.2, an aminoalkyl group or
an alkylamino group.
[0185] Compounds of formula I useful in the methods described
herein include compounds as substantially described hereinabove. In
certain instances, the compound of formula I used to treat cancer
in the methods provided herein includes compounds where R.sup.1,
R.sup.2, and R.sup.3 are hydrogen. In certain instances Y is
--C(O)NH--CH.sub.2--. In certain instances, R.sup.3 can be
C.sub.1-C.sub.4 alkyl as described above. A of formula I can be a 5
to 10-membered heterocyclic moiety. In particular, and as described
above, useful embodiments of the compound of formula I include
compounds where A is N-heterocycle, such as for example, a 5 or 6
membered heterocyclic moiety. A can be, in certain instances, a
pyridinyl.
[0186] The compound of formula I useful in the methods described
herein can be a compound where R.sup.4 is --NH.sub.2 amount of 0.1
mg/kg, 0.3 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 5 mg/kg, 10 mg/kg, or
20 mg/kg and at least of X.sup.1, X.sup.2, X.sup.3, or X.sup.4 is
--NH.sub.2 or halogen. In certain instances, the compound of
formula I for use in the methods described herein includes
compounds where R.sup.4 is --NH.sub.2 and at least one of X.sup.1,
X.sup.2, X.sup.3, or X.sup.4 is halogen (e.g., --F). In one
embodiment, the compound of formula I is a compound having the
structure of formula Ia as set forth above.
[0187] The PD-L1 inhibitors, PD-1 inhibitors, and CTLA-4 inhibitors
for use in the methods described herein are those inhibitors
described herein. For example, the PD-L1 inhibitors, PD-1
inhibitors, and CTLA-4 inhibitors can be a small molecule compound,
a nucleic acid, a polypeptide, an antibody, a peptibody, a diabody,
a minibody, a single-chain variable fragment (ScFv), or functional
fragment or variant thereof. In other examples, the inhibitor can
be an Inhibitor Antibody as set forth above.
Target Cancers
[0188] The cancer can be a solid tumor. The cancer can be a
hematological cancer. In certain instances, the cancer is a solid
tumor selected from the group consisting of squamous cell
carcinoma, non-squamous cell carcinoma, non-small cell lung cancer
(NSCLC), small cell lung cancer, melanoma, hepatocellular
carcinoma, renal cell carcinoma, ovarian cancer, head and neck
cancer, urothelial cancer, breast cancer, prostate cancer,
glioblastoma, colorectal cancer, pancreatic cancer, lymphoma,
leiomyosarcoma, liposarcoma, synovial sarcoma, or malignant
peripheral sheath tumor (MPNST).
[0189] In particular embodiments, the cancer is a solid tumor
selected from non-small cell lung cancer (NSCLC), hepatocellular
carcinoma, melanoma, ovarian cancer, breast cancer, pancreatic
cancer, renal cell carcinoma, or colorectal cancer. The cancer can
be non-small cell lung cancer (NSCLC). The cancer can be
hepatocellular carcinoma. The cancer can be melanoma. The cancer
can be ovarian cancer. The cancer can be breast cancer. The cancer
can be pancreatic cancer. The cancer can be renal cell carcinoma.
The cancer can be colorectal cancer.
[0190] Provided herein are methods of treating NSCLC by
administering a therapeutically effective amount of a combination
described herein where the combination includes a compound of
formula I and an Inhibitor Antibody. In some embodiments, the NSCLC
is Stage IIA or Stage IIB. The NSCLC can be a Stage IIIA or Stage
IIIB cancer. The NSCLC can be a Stage IV cancer. Staging of cancers
as described herein is described by the American Joint Committee on
Cancer TNM classification of malignant tumors cancer staging
notation as is well understood in the art. Those of skill in the
art will readily understand other staging classification systems
are available and applicable to the methods described herein. In
certain instances, the method is a method of treating Stage IIIA or
IIIB NSCLC by administering a combination described herein that
includes a compound of formula I and an Inhibitor Antibody.
[0191] Still further provided herein are methods of treating
melanoma by administering a therapeutically effective amount of a
combination described herein where the combination includes a
compound of formula I and an Inhibitor Antibody. In some
embodiments the melanoma is a Stage IIA, IIB, or IIC cancer. In
another embodiment, the melanoma is a Stage IIIA, Stage IIIB, or
Stage IIIC cancer. In still another embodiment, the melanoma is a
Stage IV cancer. In one aspect the method is a method of treating
Stage II (e.g., Stage IIA, IIB, or IIC) melanoma by administering a
therapeutically effective amount of a combination described herein
where the combination includes a compound of formula I and an
Inhibitor Antibody.
[0192] Also provided herein are methods of treating breast cancer
by administering a therapeutically effective amount of a
combination described herein where the combination includes a
compound of formula I and an Inhibitor Antibody. The breast cancer
can be HER2 negative breast cancer. The breast cancer can be a HER2
positive breast cancer. The breast cancer can be triple-negative
breast cancer. In some embodiments the breast cancer is a Stage IA
or Stage D3 cancer. In another embodiment, the breast cancer is a
Stage IIA or Stage IIB cancer. In still another embodiment, the
breast cancer is a Stage IIIA, Stage IIIB, or Stage IIIC cancer. In
yet another embodiment, the breast cancer is a Stage IV cancer.
[0193] In other embodiments, the cancer is a hematological cancer
selected from lymphoma, Non-Hodgkin's lymphoma (NHL), Hodgkin's
Lymphoma, Reed-Sternberg disease, multiple myeloma (MM), acute
myelogenous leukemia (AML), chronic myelogenous leukemia (CIVIL),
acute lymphocytic leukemia, (ALL), or chronic lymphocytic leukemia
(CLL). In certain embodiments, the cancer is Hodgkin's Lymphoma or
Reed-Sternberg disease.
[0194] The combinations described herein can be administered to a
cancer patient at any time following diagnosis. For example, the
cancer patient can be treatment naive (e.g., has not received a
cancer therapy for the diagnosed cancer). The cancer patient can be
treatment naive for one cancer but can be diagnosed with one or
more other cancers resulting from, for example, metastasis or
malignancy. The cancer patient can be immune checkpoint naive for
one or more cancers. The cancer patient can have a cancer that is
refractory. In certain instances, the combinations described herein
are administered as a first line therapy (e.g., the first therapy
administered to a treatment naive cancer patient) to a patient in
need thereof
[0195] However, cancer morbidity and mortality is often associated
with ineffective therapy or a cancer gaining resistant to or
becoming refractory to one or more cancer therapies. The
combinations described herein can, therefore, be administered to
patients in need thereof as a second, third, fourth, fifth, sixth,
or more line of treatment. The combinations described herein can be
administered to a cancer patient who has been treated with at least
one anti-cancer therapy or anti-cancer agent. In certain instances
the patient has received at least one anti-cancer therapy
including, for example, chemotherapy, radiotherapy, surgery,
targeted therapy, immunotherapy, or a combination thereof. The
patient can have a cancer that is resistant/refractory to treatment
with at least one anti-cancer agent.
[0196] The methods of treating cancers herein include treating
subjects who have been treated with a checkpoint inhibitor and have
experienced no response to treatment, or a partial response, or
stable disease, but then develop resistance to treatment with
progression of disease or who have experienced a complete response
to treatment, but then develop resistance to treatment with
progression of disease (as defined by RECIST or other criteria).
Resistance is defined as disease progression during treatment or a
lack of response to treatment. Such Inhibitor Antibody treatment
failures can be treated with an Inhibitor Antibody in combination
with an HDAC inhibitor, such as, without limitation, HBI-8000 or an
HDAC inhibitor that inhibits cancer-associated Class I HDAC
selected from one or more of HDAC1, HDAC2, or HDAC3. In some
instances the HDAC inhibitor also inhibits Class IIb HDAC1.
[0197] Response Criteria
[0198] Recist:
[0199] RECIST is a set of established criteria or standards,
internationally recognized for evaluating patient response,
stability and progression in clinical trials and in the clinical
practice. Originally published in 2000, and revised in 2009
(Eisenhauer E A, et al.; New response criteria in solid tumors:
revised RECIST guideline (version 1.1); Eur J Cancer 2009;
45:228-47), as a joint effort of the European Organization for
Research and Treatment of Cancer, the National Cancer Institute of
the United States and the National Cancer Institute of Canada
Clinical Trials Group, RECIST has traditionally been utilized in
the evaluation of response to chemotherapy.
[0200] Evaluation of Target Lesions:
[0201] Complete Response (CR): Disappearance of all target lesions;
Partial Response (PR): At least a 30% decrease in the sum of the LD
(longest diameter) of target lesions, taking as reference the
baseline sum LD; Stable Disease (SD): Neither sufficient shrinkage
to qualify for PR nor sufficient increase to qualify for PD, taking
as reference the smallest sum LD since the treatment started;
Progressive Disease (PD): At least a 20% increase in the sum of the
LD of target lesions, taking as reference the smallest sum LD
recorded since the treatment started or the appearance of one or
more new lesions.
[0202] Evaluation of Non-Target Lesions
[0203] Complete Response (CR): Disappearance of all non-target
lesions and normalization of tumor marker level; Incomplete
Response/Stable Disease (SD): Persistence of one or more non-target
lesion(s) or/and maintenance of tumor marker level above the normal
limits; Progressive Disease (PD): Appearance of one or more new
lesions and/or unequivocal progression of existing non-target
lesions.
[0204] Other Response Criteria
[0205] Other response criteria include the Immune-Related Response
Criteria or iRECIST, as defined by Wolchok et al., in 2009 (Wolchok
J D, et al.; Guidelines for the Evaluation of Immune Therapy
Activity in Solid Tumors: Immune-Related Response Criteria. Clin
Cancer Res 2009; 15(23):7412-20) and the revised International
Working Group Response Criteria (Cheson B D et al., Revised
response criteria for malignant lymphoma. J. Clin. Oncol. 2007;
25:579-586).
[0206] The methods of treating cancer include methods for
inhibiting cell growth by administering a therapeutically effective
amount of a combination described herein where the combination
includes a compound of formula I and a PD-L1 inhibitor and/or PD-1
inhibitor, plus a CTLA-4 inhibitor described herein.
[0207] Also provided herein are methods of inhibiting metastasis of
a cancer in a patient in need thereby by administering a
therapeutically effective amount of a combination described herein
where the combination includes a compound of formula I and a PD-L1
inhibitor and/or PD-1 inhibitor, plus a CTLA-4 inhibitor described
herein. In some embodiments, metastasis is inhibited by at least
about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%.
[0208] In another aspect is a method of reducing pre-existing tumor
metastasis in a cancer patient in need thereof by administering a
therapeutically effective amount of a combination described herein
where the combination includes a compound of formula I and a PD-L1
inhibitor and/or PD-1 inhibitor, plus a CTLA-4 inhibitor described
herein. In some embodiments, pre-existing tumor metastasis is
reduced by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%,
80%, 90%, or 100%.
[0209] In still another aspect the methods of treating cancer also
provide for methods for reducing tumor burden in an individual by
administering a therapeutically effective amount of a combination
described herein where the combination includes a compound of
formula I and a PD-L1 inhibitor and/or PD-1 inhibitor, plus a
CTLA-4 inhibitor described herein. In some embodiments, tumor
burden is reduced by at least about 5%, 10%, 20%, 30%, 40%, 50%,
60%, 70%, 80%, 90%, or 100%.
[0210] In another aspect the methods of treating cancer also
provide for methods for reducing tumor burden in an individual by
administering a therapeutically effective amount of a combination
described herein where the combination includes a compound of
formula I and a PD-L1 inhibitor and/or PD-1 inhibitor, plus a
CTLA-4 inhibitor described herein. In some embodiments, tumor
burden is reduced by at least about 5%, 10%, 20%, 30%, 40%, 50%,
60%, 70%, 80%, 90%, or 100%.
[0211] The methods of treating cancer described herein also provide
for methods for increasing or otherwise prolonging time to disease
progression of certain stages (including advanced stages of cancer
such as Stage III and IV cancer described herein). Time to disease
progression can be prolonged in a patient by administering a
therapeutically effective amount of a combination described herein
where the combination includes a compound of formula I and a PD-L1
inhibitor and/or PD-1 inhibitor, plus a CTLA-4 inhibitor described
herein. In some embodiments, the increase is a comparison between
the time to disease progression without treatment and with
treatment with a combination described herein. In some embodiments,
the methods described herein prolong the time to disease
progression by at least 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month,
2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8
months, 9 months, 10 months, 11 months, 1 year, or more, including
values therein.
[0212] The methods of treating cancer described herein also provide
for methods for increasing or otherwise prolonging survival
(including overall survival) of patients diagnosed with cancer as
described herein. Patient survival can be prolonged by
administering a therapeutically effective amount of a combination
described herein where the combination includes a compound of
formula I and a PD-L1 inhibitor and/or PD-1 inhibitor, plus a
CTLA-4 inhibitor described herein. In some embodiments, the
increase is a comparison between the survival without treatment and
with treatment with a combination as described herein. In some
embodiments, the methods described herein prolong survival by at
least 1 week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3
months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months,
10 months, 11 months, 1 year, 2 years, or more, including values
therein.
[0213] The methods of treating cancer described herein also provide
for methods for increasing progression-free survival of patients
diagnosed with cancer as described herein. Patient progression-free
survival can be prolonged by administering a therapeutically
effective amount of a combination described herein where the
combination includes a compound of formula I and a PD-L1 inhibitor
and/or PD-1 inhibitor, plus a CTLA-4 inhibitor described herein. In
some embodiments, the increase is a comparison between the
progression-free survival without treatment and with treatment with
a combination as described herein. In some embodiments, the methods
described herein increase progression-free survival by at least 1
week, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, 4
months, 5 months, 6 months, 7 months, 8 months, 9 months, 10
months, 11 months, 1 year, 2 years, or more, including values
therein.
[0214] Also provided herein are methods of reducing a level of
myeloid-derived suppressor cells (MDSC) in a patient in need
thereof by administering an effective amount of a combination
described herein where the combination includes a compound of
formula I and a PD-L1 inhibitor and/or PD-1 inhibitor, plus a
CTLA-4 inhibitor described herein. The reduction of MDSC can
benefit the treatment of a cancer described herein. The level of
MDSC in a human patient can be measured before, during, and after
administration of a combination described herein. In some
embodiments, it can be useful to compare pre- and
post-administration amounts of MDSC in the patient. A reduction in
the amount, level, or number of MDSC following administration can
indicate effectiveness of the combination in, for example, treating
a cancer described herein. MD SC levels can be monitored over the
course of a treatment or regimen described herein with a
combination described herein. In such instances, the determination
of MD SC levels at various points during the course of
administration can indicate the effectiveness of the regimen.
[0215] Methods of reducing the percentage or level of Treg cells in
a patient in need thereof are also provided herein. Such methods
include administering an effective amount of a combination
described herein where the combination includes a compound of
formula I and a PD-L1 inhibitor and/or PD-1 inhibitor, plus a
CTLA-4 inhibitor described herein. The reduction of Treg cells can
benefit the treatment of a cancer described herein. The level of
Treg cells in a human patient can be measured before, during, and
after administration of a combination described herein. In some
embodiments, it can be useful to compare pre- and
post-administration amounts of Treg cells in the patient. A
reduction in the amount, level, or number of Treg cells following
administration can indicate effectiveness of the combination in,
for example, treating a cancer described herein. Treg cell levels
can be monitored over the course of a treatment or regimen
described herein with a combination described herein. In such
instances, the determination of Treg cell levels at various points
during the course of administration can indicate the effectiveness
of the regimen.
[0216] The combinations described herein can be useful in methods
of enhancing activity of natural killer (NK) cells. The
combinations described herein can also be useful in methods of
enhancing activity of cytotoxic T-cells. The methods of enhancing
include contacting a NK cell or cytotoxic T-cell with a combination
described herein where the combination enhances the activity of the
NK cell or cytotoxic T-cell relative to its activity prior to the
contact. In some embodiments, the enhanced activity of the NK cell
or cytotoxic T-cell is in a cancer patient who has been
administered a combination as described herein.
[0217] The combinations described herein can also enhance
antibody-dependent cell-mediated cytotoxicity in a cancer patient
upon administration of a combination as described herein.
[0218] The combinations described herein can include administration
of each therapy (e.g., a compound of formula I and a PD-L1
inhibitor and/or PD-1 inhibitor, plus a CTLA-4 inhibitor), where
the administration is performed simultaneously or sequentially (in
either order). In one embodiment, the compound of formula I and the
PD-L1 inhibitor and/or PD-1 inhibitor, plus a CTLA-4 inhibitor are
administered simultaneously (e.g., within at least 1 to 5 min of
each other). In another embodiment, the compound of formula I and
the PD-L1 inhibitor and/or PD-1 inhibitor, plus a CTLA-4 inhibitor
are administered sequentially (e.g., within at least 10 min, 15
min, 30 min, 1 h, 2 h, 5 h, 10 h, 12 h, 1 day, 2 days, 5 days, 7
days, 14 days, or 21 days of each other).
[0219] The compound of formula I can be administered, for example,
once a day (QD), twice daily (BID), once a week (QW), twice weekly
(BIW), three times a week (TIW), or monthly (QM) regularly on a
continuous base or intermittent base such as BIW for 3 months then
resume a month later. For example, the compound of formula I can be
administered BID. The compound of formula I can be administered
TIW. In certain instances, the compound of formula I is
administered 2 to 3 times a week. In another embodiment, the
compound of formula I is administered QD. The compound can be
administered QD for about: 1 day to about 7 days, 1 day to about 14
days, 1 day to about 21 days, 1 day to about 28 days, or daily
until disease progression or unacceptable toxicity. The
administration of a compound of formula I can, in part, depend upon
the tolerance of the patient where greater tolerance can allow
greater or more frequent administration. Alternatively, where a
patient shows poor tolerance to a compound of formula I, a less
amount of the compound or a less frequent dosing can be performed.
Compounds of formula I can be administered in any regimen as
described herein.
[0220] For example, a compound of formula I can be administered at
an amount of about: 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20
mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg,
85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg, QD. For
example, a compound of formula I can be administered at an amount
of about: 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg,
30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90
mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg, BIW. For example, a
compound of formula I can be administered at an amount of about: 1
mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35
mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg,
125 mg, 150 mg, 175 mg, or 200 mg, TIW. For example, a compound of
formula I can be administered at an amount of about: 1 mg, 2 mg, 3
mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45
mg, 50 mg, 60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150
mg, 175 mg, or 200 mg, QW. For example, a compound of formula I can
be administered at an amount of about: 1 mg, 2 mg, 3 mg, 4 mg, 5
mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg,
60 mg, 70 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg,
or 200 mg, Q2W. For example, a compound of formula I can be
administered at an amount of about 5 mg or about 10 mg, QD. For
example, a compound of formula I can be administered at an amount
of about 5 mg or about 10 mg, BIW. For example, a compound of
formula I can be administered at an amount of about 5 mg or about
10 mg, TIW. For example, a compound of formula I can be
administered at an amount of about 5 mg or about 10 mg, QW. For
example, a compound of formula I can be administered at an amount
of about 5 mg or about 10 mg, Q2W. Administration of a compound of
formula I can be continuous. Administration of a compound of
formula I can be intermittent.
[0221] For example, a compound of formula I can be administered at
an amount of about: 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg
to about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to
about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to
about 100 mg, or 100 mg to about 200 mg, QD. For example, a
compound of formula I can be administered at an amount of about: 1
mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg
to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to
about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, or 100 mg
to about 200 mg, BIW. For example, a compound of formula I can be
administered at an amount of about: 1 mg to about 10 mg, 1 mg to
about 25 mg, 1 mg to about 50 mg, 5 mg to about 10 mg, 5 mg to
about 25 mg, 5 mg to about 50 mg, 10 mg to about 25 mg, 10 mg to
about 50 mg, 50 mg to about 100 mg, or 100 mg to about 200 mg, TIW.
For example, a compound of formula I can be administered at an
amount of about: 1 mg to about 10 mg, 1 mg to about 25 mg, 1 mg to
about 50 mg, 5 mg to about 10 mg, 5 mg to about 25 mg, 5 mg to
about 50 mg, 10 mg to about 25 mg, 10 mg to about 50 mg, 50 mg to
about 100 mg, or 100 mg to about 200 mg, QW. For example, a
compound of formula I can be administered at an amount of about: 1
mg to about 10 mg, 1 mg to about 25 mg, 1 mg to about 50 mg, 5 mg
to about 10 mg, 5 mg to about 25 mg, 5 mg to about 50 mg, 10 mg to
about 25 mg, 10 mg to about 50 mg, 50 mg to about 100 mg, or 100 mg
to about 200 mg, Q2W. Administration of a compound of formula I can
be continuous. Administration of a compound of formula I can be
intermittent.
[0222] r example, a compound of formula I can be administered at an
amount of about: 0.0001 mg/kg to about 200 mg/kg, 0.001 mg/kg to
about 200 mg/kg, 0.01 mg/kg to about 200 mg/kg, 0.01 mg/kg to about
150 mg/kg, 0.01 mg/kg to about 100 mg/kg, 0.01 mg/kg to about 50
mg/kg, 0.01 mg/kg to about 25 mg/kg, 0.01 mg/kg to about 10 mg/kg,
or 0.01 mg/kg to about 5 mg/kg, 0.05 mg/kg to about 200 mg/kg, 0.05
mg/kg to about 150 mg/kg, 0.05 mg/kg to about 100 mg/kg, 0.05 mg/kg
to about 50 mg/kg, 0.05 mg/kg to about 25 mg/kg, 0.05 mg/kg to
about 10 mg/kg, or 0.05 mg/kg to about 5 mg/kg, 0.5 mg/kg to about
200 mg/kg, 0.5 mg/kg to about 150 mg/kg, 0.5 mg/kg to about 100
mg/kg, 0.5 mg/kg to about 50 mg/kg, 0.5 mg/kg to about 25 mg/kg,
0.5 mg/kg to about 10 mg/kg, or 0.5 mg/kg to about 5 mg/kg, QD. For
example, a compound of formula I can be administered at an amount
of about: 0.0001 mg/kg to about 200 mg/kg, 0.001 mg/kg to about 200
mg/kg, 0.5 mg/kg to about 200 mg/kg, 0.5 mg/kg to about 150 mg/kg,
0.5 mg/kg to about 100 mg/kg, 0.5 mg/kg to about 50 mg/kg, 0.5
mg/kg to about 25 mg/kg, 0.5 mg/kg to about 10 mg/kg, or 0.5 mg/kg
to about 5 mg/kg, BIW. For example, a compound of formula I can be
administered at an amount of about: 0.0001 mg/kg to about 200
mg/kg, 0.001 mg/kg to about 200 mg/kg, 0.5 mg/kg to about 200
mg/kg, 0.5 mg/kg to about 150 mg/kg, 0.5 mg/kg to about 100 mg/kg,
0.5 mg/kg to about 50 mg/kg, 0.5 mg/kg to about 25 mg/kg, 0.5 mg/kg
to about 10 mg/kg, or 0.5 mg/kg to about 5 mg/kg, TIW. For example,
a compound of formula I can be administered at an amount of about:
0.0001 mg/kg to about 200 mg/kg, 0.001 mg/kg to about 200 mg/kg,
0.5 mg/kg to about 200 mg/kg, 0.5 mg/kg to about 150 mg/kg, 0.5
mg/kg to about 100 mg/kg, 0.5 mg/kg to about 50 mg/kg, 0.5 mg/kg to
about 25 mg/kg, 0.5 mg/kg to about 10 mg/kg, or 0.5 mg/kg to about
5 mg/kg, QW. For example, a compound of formula I can be
administered at an amount of about: 0.0001 mg/kg to about 200
mg/kg, 0.001 mg/kg to about 200 mg/kg, 0.5 mg/kg to about 200
mg/kg, 0.5 mg/kg to about 150 mg/kg, 0.5 mg/kg to about 100 mg/kg,
0.5 mg/kg to about 50 mg/kg, 0.5 mg/kg to about 25 mg/kg, 0.5 mg/kg
to about 10 mg/kg, or 0.5 mg/kg to about 5 mg/kg, Q2W. In one
example, a compound of formula I can be administered at an amount
of about 15 mg/kg to about 75 mg/kg, QD. In another example, a
compound of formula I can be administered at an amount of about 20
mg/kg to about 50 mg/kg. In still another example, a compound of
formula I can be administered at an amount of about 0.001 mg/kg,
0.01 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3
mg/kg, 4 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30
mg/kg, 40 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg,
100 mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg, or 200 mg/kg.
Administration of a compound of formula I can be continuous.
Administration of a compound of formula I can be intermittent.
[0223] For example, a compound of formula I can be administered at
an amount of about: 1 mg/kg to about 200 mg/kg, 1 mg/kg to about
150 mg/kg, 1 mg/kg to about 100 mg/kg, 1 mg/kg to about 50 mg/kg, 1
mg/kg to about 25 mg/kg, 1 mg/kg to about 10 mg/kg, or 1 mg/kg to
about 5 mg/kg, QD. For example, a compound of formula I can be
administered at an amount of about: 1 mg/kg to about 200 mg/kg, 1
mg/kg to about 150 mg/kg, 1 mg/kg to about 100 mg/kg, 1 mg/kg to
about 50 mg/kg, 1 mg/kg to about 25 mg/kg, 1 mg/kg to about 10
mg/kg, or 1 mg/kg to about 5 mg/kg, BIW. For example, a compound of
formula I can be administered at an amount of about: 1 mg/kg to
about 200 mg/kg, 1 mg/kg to about 150 mg/kg, 1 mg/kg to about 100
mg/kg, 1 mg/kg to about 50 mg/kg, 1 mg/kg to about 25 mg/kg, 1
mg/kg to about 10 mg/kg, or 1 mg/kg to about 5 mg/kg, TIW. For
example, a compound of formula I can be administered at an amount
of about: 1 mg/kg to about 200 mg/kg, 1 mg/kg to about 150 mg/kg, 1
mg/kg to about 100 mg/kg, 1 mg/kg to about 50 mg/kg, 1 mg/kg to
about 25 mg/kg, 1 mg/kg to about 10 mg/kg, or 1 mg/kg to about 5
mg/kg, QW. For example, a compound of formula I can be administered
at an amount of about: 1 mg/kg to about 200 mg/kg, 1 mg/kg to about
150 mg/kg, 1 mg/kg to about 100 mg/kg, 1 mg/kg to about 50 mg/kg, 1
mg/kg to about 25 mg/kg, 1 mg/kg to about 10 mg/kg, or 1 mg/kg to
about 5 mg/kg, Q2W. In one example, a compound of formula I can be
administered at an amount of about 15 mg/kg to about 75 mg/kg, QD.
In another example, a compound of formula I can be administered at
an amount of about 20 mg/kg to about 50 mg/kg. In still another
example, a compound of formula I can be administered at an amount
of about 0.001 mg/kg, 0.01 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.5 mg/kg,
1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20
mg/kg, 25 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg,
80 mg/kg, 90 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg, or
200 mg/kg. Administration of a compound of formula I can be
continuous. Administration of a compound of formula I can be
intermittent.
[0224] As used herein, the term daily is intended to mean that a
therapeutic compound of a combination described herein, such as a
compound of formula I, is administered once or more than once each
day for a period of time. The term continuous is intended to mean
that a therapeutic compound of a combination described herein, such
as a compound of formula I, is administered daily for an
uninterrupted period of at least 10 days to 52 weeks. The term
intermittent or intermittently as used herein is intended to mean
stopping and starting at either regular or irregular intervals. For
example, intermittent administration of a therapeutic compound of a
combination described herein, such as a compound of formula I,
includes administration for one to six days per week (e.g., 2 to 3
times per week or QD), administration in cycles (e.g., daily
administration for two to eight consecutive weeks, then a rest
period with no administration at least one day), or, for example,
administration on alternate days.
[0225] Where the inhibitor is an Inhibitor Antibody, it can be
administered according to established regimens such as those
provided in a package insert. The Inhibitor Antibody can be
administered in an amount described herein and can be administered
QW, once every 2 weeks (Q2W), once every 3 weeks (Q3W), or once
every 4 weeks (Q4W). In one embodiment, the Inhibitor Antibody is
administered Q2W or Q4W. In another embodiment, the Inhibitor
Antibody is administered Q2W. In yet another embodiment, the
Inhibitor Antibody is administered Q3W. In still another
embodiment, the Inhibitor Antibody is administered BIW for at least
3 weeks. In still another embodiment, the Inhibitor Antibody is
administered Q4W.
[0226] For example, the Inhibitor Antibody can be administered at
an amount of about 0.1 mg/kg to about 30 mg/kg (including for
example 0.1 mg/kg, 0.3 mg/kg, 0.5 mg/kg, 0.7 mg/kg, 1 mg/kg, 2
mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 10
mg/kg, 12 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg), QW. For
example, the Inhibitor Antibody can be administered at an amount of
about 0.1 mg/kg to about 30 mg/kg (including for example 0.1 mg/kg,
0.3 mg/kg, 0.5 mg/kg, 0.7 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4
mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 10 mg/kg, 12 mg/kg, 15
mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg), Q2W. For example, the
Inhibitor Antibody can be administered at an amount of about 0.1
mg/kg to about 30 mg/kg (including for example 0.1 mg/kg, 0.3
mg/kg, 0.5 mg/kg, 0.7 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5
mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 10 mg/kg, 12 mg/kg, 15 mg/kg, 20
mg/kg, 25 mg/kg, 30 mg/kg), Q4W. For example, the Inhibitor
Antibody can be administered at an amount of about 0.1 mg/kg to
about 30 mg/kg (including for example 0.1 mg/kg, 0.3 mg/kg, 0.5
mg/kg, 0.7 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6
mg/kg, 7 mg/kg, 8 mg/kg, 10 mg/kg, 12 mg/kg, 15 mg/kg, 20 mg/kg, 25
mg/kg, 30 mg/kg), B4W (twice every 4 weeks). For example, the
Inhibitor Antibody can be administered at an amount of about 0.1
mg/kg to about 30 mg/kg (including for example 0.1 mg/kg, 0.3
mg/kg, 0.5 mg/kg, 0.7 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5
mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 10 mg/kg, 12 mg/kg, 15 mg/kg, 20
mg/kg, 25 mg/kg, 30 mg/kg), Q3W. For example, the Inhibitor
Antibody can be administered at an amount of about 1000 mg to about
2000 mg (including for example 1000 mg, 1100 mg, 1200 mg, 1300 mg,
1400 mg, 1500 mg, 1600 mg), Q2W. For example, the Inhibitor
Antibody can be administered at an amount of about 1000 mg to about
2000 mg (including for example 1000 mg, 1100 mg, 1200 mg, 1300 mg,
1400 mg, 1500 mg, 1600 mg), Q3W. For example, the Inhibitor
Antibody can be administered at an amount of about 1000 mg to about
2000 mg (including for example 1000 mg, 1100 mg, 1200 mg, 1300 mg,
1400 mg, 1500 mg, 1600 mg), Q4W. Administration of the Inhibitor
Antibody can be continuous. Administration of the Inhibitor
Antibody can be intermittent.
[0227] The Inhibitor Antibody can be administered as an intravenous
infusion over about 10, 20, 30, 40, 50, or 60 or more minutes. the
Inhibitor Antibody can be administered as an intravenous infusion
over about 60 minutes once every 1, 2, 3, 4, 5 or more weeks. the
Inhibitor Antibody can be administered as an intravenous infusion
over about 60 minutes once every two weeks. the Inhibitor Antibody
can be administered as an intravenous infusion over about 60
minutes once every three weeks. the Inhibitor Antibody can be
administered as an intravenous infusion over about 60 minutes once
every four weeks. the Inhibitor Antibody can be administered as an
intravenous infusion according to a package insert. Administration
of Inhibitor Antibody can be continuous. Administration of
Inhibitor Antibody can be intermittent.
[0228] The combinations described herein can be administered in a
regimen. The regimen can be structured to provide therapeutically
effective amounts of a compound of formula I and an inhibitor, such
as an Inhibitor Antibody, over a predetermined period of time
(e.g., an administration time). The regimen can be structured to
limit or prevent side-effects or undesired complications of each of
the components of the combination described herein. The regimen can
be structured in a manner that results in increased effect for both
therapies of the combination (e.g., synergy). Regimens useful for
treating cancer can include any number of days of administration
which can be repeated as necessary. Administration periods can be
broken by a rest period that includes no administration of at least
one therapy. For example, a regimen can include administration
periods that include 2, 3, 5, 7, 10, 15, 21, 28, or more days.
These periods can be repeated. For example, a regimen can include a
set number of days as previously described where the regimen is
repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or more
times.
[0229] Regimens can include a rest period of at least 1, 2, 3, 5,
7, 10, or more days, where at least one therapy is no longer
administered to a patient. The rest period can be determined by,
for example, monitoring the reaction of the patient to the drug or
by measuring the efficacy of the treatment. A rest period can be
applicable to a single therapy, such that only one therapy of a
combination described herein is discontinued in the rest period but
the other therapy(ies) are still administered. Rest periods can be
applied to all of the therapies administered to the subject such
that the subject receives no therapy for a set period of time
during the rest period.
[0230] Regimens described herein for the treatment of cancer using
the combinations described herein can be continued until disease
progression or unacceptable toxicity.
[0231] Regimens for administration of combinations described herein
include, for example administration of a compound of formula I BIW
or TIW and administration of a PD-L1 and/or PD-1 inhibitor, plus
CTLA-4 inhibitor. For example, a compound of formula I can be
administered QD for about 21 days and an Inhibitor Antibody
described herein can be administered Q2W or Q4W). For example, a
compound of formula I can be administered BIW or TIW and an
Inhibitor Antibody described herein can be administered Q2W. In
another exemplary regimen, a compound of formula I can be
administered BIW or TIW and an Inhibitor Antibody can be
administered BIW for 2 or 3 weeks. In still another exemplary
regimen, a compound of formula I can be administered BIW or TIW and
an Inhibitor Antibody can be administered Q4W. In still another
exemplary regimen, a compound of formula I can be administered BIW
and an inhibitor described herein can be administered Q2W, Q3W, or
Q4W. In certain instances, such regimens include administration of
an Inhibitor Antibody administered Q2W, Q3W, or Q4W. In yet another
exemplary regimen, a compound of formula I can be administered TIW
and an inhibitor described herein can be administered Q2W, Q3W, or
Q4W. In certain instances, such regimens include administration of
an Inhibitor Antibody administered Q2W, Q3W, or Q4W. In certain
instances, such regimens include administration of a compound of
formula I administered QD. In certain instances, such regimens
include administration of a compound of formula I administered QD
for at least 21 days. In yet another exemplary regimen, a compound
of formula I can be administered QD or QW and an inhibitor (e.g.,
an Inhibitor Antibody) is administered Q2W, Q3W, or Q4W.
[0232] The regimen can be a regimen for administration of an
Inhibitor Antibody with a compound of formula I as described
herein. In one exemplary regimen including an Inhibitor Antibody, a
compound of formula I can be administered BIW or TIW and an
Inhibitor Antibody is administered in accordance with the
prescribing information provided in, for example, a package insert.
In another exemplary regimen, an Inhibitor Antibody is administered
at an amount of about 1 mg/kg to about 20 mg/kg on day 1 of the
regimen, and Q2W thereafter until disease progression or
unacceptable toxicity and a compound of formula I is administered
BIW or TIW over the same period of time. In another exemplary
regimen, an Inhibitor Antibody is administered at an amount of
about 1 mg/kg to about 20 mg/kg on day 1 of a regimen, and Q3W
thereafter until disease progression or unacceptable toxicity and a
compound of formula I is administered BIW or TIW over the same
period of time. an Inhibitor Antibody can be administered Q4W with
a compound of formula I, where the compound of formula I is
administered, for example, BIW or TIW during the course of such a
regimen. an Inhibitor Antibody can be administered Q2W with a
compound of formula I, where the compound of formula I is
administered, for example, BIW or TIW during the course of such a
regimen. In still another exemplary regimen, an Inhibitor Antibody
can be administered Q2W or Q4W with a compound of formula I, where
the compound of formula I is administered, for example, QD or QW
during the course of such a regimen. Such regimens can be repeated
as described above (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or
more times).
[0233] In another exemplary regimen including an Inhibitor
Antibody, a compound of formula I can be administered QD and an
Inhibitor Antibody is administered in accordance with the
prescribing information provided in, for example, a package insert.
In another exemplary regimen, an Inhibitor Antibody is administered
at an amount of about 1 mg/kg to about 20 mg/kg on day 1 of the
regimen, and Q2W thereafter until disease progression or
unacceptable toxicity and a compound of formula I is administered
QD over the same period of time. In another exemplary regimen, an
Inhibitor Antibody is administered at an amount of about 1 mg/kg to
about 20 mg/kg on day 1 of a regimen, and Q3W thereafter until
disease progression or unacceptable toxicity and a compound of
formula I is administered QD over the same period of time. an
Inhibitor Antibody can be administered Q4W with a compound of
formula I, where the compound of formula I is administered QD
during the course of such a regimen. an Inhibitor Antibody can be
administered Q2W with a compound of formula I, where the compound
of formula I is administered QD during the course of such a
regimen. Such regimens can be repeated as described above (e.g., 1,
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more times).
[0234] It should also be appreciated that the combinations
described herein for treating cancer can be coadministered with
other active agents other than those present in the combinations
described herein (e.g., anti-cancer agents). Regimens for
administration of a combination described herein, including the
exemplary regimens set forth above, can be modified as necessary to
include administration of such active agents. Administration of
such active agents, e.g., anti-cancer agents, can be performed QD,
QW, QM, BID, BIW, TIW, Q2W, Q3W, or Q4W, or in accordance with
prescribing information for such anti-cancer agents as set forth,
for example, in a package insert. Exemplary anti-cancer agents
include but are not limited to: ABRAXANE; abiraterone; ace-11;
aclarubicin; acivicin; acodazole hydrochloride; acronine;
actinomycin; acylfulvene; adecypenol; adozelesin; adriamycin;
aldesleukin; all trans-retinoic acid (ATRA); altretamine;
ambamustine; ambomycin; ametantrone acetate; amidox; amifostine;
aminoglutethimide; aminolevulinic acid; amrubicin; amsacrine;
anagrelide; anastrozole; andrographolide; antarelix; anthramycin;
aphidicolin glycinate; apurinic acid; ara-CDP-DL-PTBA; arginine
deaminase; ARRY-162; ARRY-300; ARRY-142266; AS703026; asparaginase;
asperlin; asulacrine; atamestane; atrimustine; axinastatin 1;
axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine;
azacitidine; AZD8330; azetepa; azotomycin; balanol; batimastat; BAY
11-7082; BAY 43-9006; BAY 869766; bendamustine; benzochlorins;
benzodepa; benzoylstaurosporine; beta-alethine; betaclamycin B;
betulinic acid; b-FGF inhibitor; bicalutamide; bisantrene;
bisaziridinylspermine; bisnafide; bisnafide dimesylate; bistratene
A; bisantrene hydrochloride; bleomycin; bleomycin sulfate;
busulfan; bizelesin; breflate; bortezomib; brequinar sodium;
bropirimine; budotitane; buthionine sulfoximine; bryostatin;
cactinomycin; calusterone; calcipotriol; calphostin C; camptothecin
derivatives; capecitabine; carboxamide-amino-triazole;
carboxyamidotriazole; CaRest M3; CARN 700; caracemide; carbetimer;
carboplatin; carmustine; carubicin hydrochloride; carzelesin;
castanospermine; cecropin B; cedefingol; celecoxib; cetrorelix;
chlorins; chloroquinoxaline sulfonamide; cicaprost; chlorambucil;
Chlorofusin; cirolemycin; cisplatin; CI-1040; cis-porphyrin;
cladribine; clomifene analogues; clotrimazole; collismycin A;
collismycin B; combretastatin A4; combretastatin analogue;
conagenin; crambescidin 816; crisnatol; crisnatol mesylate;
cryptophycin 8; cryptophycin A derivatives; curacin A;
cyclopentanthraquinones; cycloplatam; cypemycin; cyclophosphamide;
cytarabine; cytarabine ocfosfate; cytolytic factor; cytostatin;
dacarbazine; dactinomycin; daunorubicin; daunorubicin
hydrochloride; decarbazine; dacliximab; dasatinib; decitabine;
dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide;
dexrazoxane; dexverapamil; dexormaplatin; dezaguanine; dezaguanine
mesylate; diaziquone; didemnin B; didox; diethylnorspermine;
dihydro 5 azacytidine; dihydrotaxol; 9-dioxamycin; diphenyl
spiromustine; docosanol; dolasetron; docetaxel; doxorubicin;
doxorubicin hydrochloride; doxifluridine; droloxifene; droloxifene
citrate; dromostanolone propionate; dronabinol; duazomycin;
duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab;
edatrexate; eflornithine hydrochloride; eflornithine; elemene;
emitefur; elsamitrucin; enloplatin; enpromate; epipropidine;
epirubicin; epirubicin hydrochloride; epristeride; erbulozole;
eribulin; esorubicin hydrochloride; estramustine; estramustine
phosphate sodium; etanidazole; etoposide; etoposide phosphate;
etoprine; exemestane; fadrozole; fadrozole hydrochloride;
fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;
flezelastine; fluasterone; floxuridine; fludarabine phosphate;
fludarabine; fluorodaunorubicin hydrochloride; forfenimex;
formestane; fluorouracil; floxouridine; flurocitabine; fosquidone;
fostriecin sodium; fostriecin; fotemustine; gadolinium texaphyrin;
gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors;
gemcitabine; geldanamycin; gossyphol; GDC-0973;
GSK1120212/trametinib; herceptin; hydroxyurea; hepsulfam;
heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;
ibrutinib; idarubicin; idarubicin hydrochloride; ifosfamide;
canfosfamide; ilmofo sine; iproplatin; idoxifene; idramantone;
ilmofo sine; ilomastat; imidazoacridones; imatinib (e.g., GLEEVEC);
imiquimod; iobenguane; iododoxorubicin; ipomeanol; irinotecan;
irinotecan hydrochloride; irsogladine; isobengazole;
isohomohalicondrin B; itasetron; iimofosine; interleukin Il
(including recombinant interleukin IL-2; or r1L.sub.2); interferon
alfa-2a; interferon alfa-2b; interferon alfa-n1; interferon
alfa-n3; interferon beta-la; interferon gamma-1b; jasplakinolide;
kahalalide F; lamellarin N triacetate; lanreotide; leinamycin;
lenograstim; lentinan sulfate; leptolstatin; letrozole;
leuprorelin; levamisole; liarozole; lissoclinamide 7; lobaplatin;
lombricine; lometrexol; lonidamine; losoxantrone; lovastatin;
loxoribine; lurtotecan; lutetium texaphyrin; lysofylline;
lanreotide acetate; lapatinib; letrozole; leucovorin; leuprolide
acetate; liarozole hydrochloride; lometrexol sodium; lomustine;
lenalidomide; lenvatinib; losoxantrone hydrochloride; LY294002;
pomalidomide; maitansine; mannostatin A; marimastat; masoprocol;
maspin; matrilysin inhibitors; menogaril; merbarone; meterelin;
methioninase; metoclopramide; MIF inhibitor; mifepristone;
miltefosine; mirimostim; mitoguazone; mitolactol; mitonafide;
mitoxantrone; mofarotene; molgramostim; mopidamol; mycaperoxide B;
myriaporone; maytansine; mechlorethamine hydrochloride; megestrol
acetate; melengestrol acetate; melphalan; mercaptopurine;
methotrexate; methotrexate sodium; metoprine; meturedepa;
mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;
mitomycin; mitosper; mitotane; mitoxantrone hydrochloride;
mycophenolic acid; nafarelin; nagrestip; napavin; naphterpin;
nartograstim; nedaplatin; nemorubicin; neridronic acid; nilutamide;
nisamycin; nitric oxide modulators; nitroxide antioxidant;
nitrullyn; nocodazole; nogalamycin; oblimersen (GENASENSE);
octreotide; okicenone; oligonucleotides; onapristone; ondansetron;
ondansetron; oracin; oral cytokine inducer; ormaplatin; oxisuran;
oxaloplatin; osaterone; oxaliplatin; oxaunomycin; palauamine;
palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene;
parabactin; pazelliptine; pegaspargase; peldesine; pentosan
polysulfate sodium; pentostatin; pentrozole; perflubron;
perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate;
phosphatase inhibitors; picibanil; pilocarpine hydrochloride;
pirarubicin; piritrexim; placetin A; placetin B; porfiromycin;
prednisone; prostaglandin J2; pyrazoloacridine; paclitaxel;
PD035901; PD184352; PD318026; PD98059; peliomycin; pentamustine;
peplomycin sulfate; PKC412; pipobroman; piposulfan; piroxantrone
hydrochloride; plicamycin; plomestane; podophyllotoxin; polyphenol
E; porfimer sodium; porfiromycin; prednimustine; procarbazine;
procarbazine hydrochloride; puromycin; puromycin hydrochloride;
pyrazofurin; raltitrexed; ramosetron; retelliptine demethylated;
rhizoxin; rituximab; RII retinamide; rogletimide; rohitukine;
romurtide; roquinimex; rubiginone B 1; ruboxyl; riboprine;
romidepsin; safingol; safingol hydrochloride; saintopin;
sarcophytol A; sargramostim; semustine; sizofiran; sobuzoxane;
sodium borocaptate; sodium phenylacetate; solverol; sonermin;
sorafenib; sunitinib; sparfosic acid; spicamycin D; spiromustine;
splenopentin; spongistatin 1; Spongistatin 2; Spongistatin 3;
Spongistatin 4; Spongistatin 5; Spongistatin 6; Spongistatin 7;
Spongistatin 8; and Spongistatin 9; squalamine; stipiamide;
stromelysin inhibitors; sulfinosine; suradista; suramin;
swainsonine; SB239063; selumetinib/AZD6244; simtrazene; SP600125;
sparfosate sodium; sparsomycin; spirogermanium hydrochloride;
spiroplatin; streptonigrin; streptozocin; sulofenur; tallimustine;
tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;
tegafur; tellurapyrylium; temoporfin; temozolomide; teniposide;
tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline;
thrombopoietin; thymalfasin; thymopoietin receptor agonist;
thymotrinan; tirapazamine; titanocene bichloride; topsentin;
toremifene; tretinoin; triacetyluridine; triciribine; trimetrexate;
triptorelin; tropisetron; turosteride; tyrphostins; talisomycin;
TAK-733; taxotere; tegafur; teloxantrone hydrochloride; teroxirone;
testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;
tirapazamine; toremifene citrate; trastuzumab; trestolone acetate;
triciribine phosphate; trimetrexate; trimetrexate glucuronate;
triptorelin; tubulozole hydrochloride; tumor necrosis
factor-related apoptosis-inducing ligand (TRAIL); UBC inhibitors;
ubenimex; U0126; uracil mustard; uredepa; vapreotide; variolin B;
velaresol; veramine; verteporfin; vinorelbine; vinxaltine; vitaxin;
vinblastine; vinblastine sulfate; vincristine sulfate; vindesine;
vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;
vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;
vinzolidine sulfate; vorozole; wortmannin; XL518; zanoterone;
zeniplatin; zilascorb; zinostatin stimalamer; zinostatin; and
zorubicin hydrochloride.
[0235] Other exemplary anti-cancer agents include Erbulozole (e.g.,
R-55104); Dolastatin 10 (e.g., DLS-10 and NSC-376128); Mivobulin
isethionate (e.g., CI-980); NSC-639829; Discodermolide (e.g.,
NVP-XX-A-296); ABT-751 (Abbott; e.g., E-7010); Altorhyrtin A;
Altorhyrtin C); Cemadotin hydrochloride (e.g., LU-103793 and
NSC-D-669356); Epothilone A; Epothilone B; Epothilone C; Epothilone
D; Epothilone E; Epothilone F; Epothilone B N-oxide; Epothilone A
N-oxide; 16-aza-epothilone B; 21-aminoepothilone B;
21-hydroxyepothilone D; 26-fluoroepothilone; Auristatin PE (e.g.,
NSC-654663); Soblidotin (e.g., TZT-1027); LS-4559-P (Pharmacia;
e.g., LS-4577); LS-4578 (Pharmacia; e.g., LS-477-P); LS-4477
(Pharmacia); LS-4559 (Pharmacia); RPR-112378 (Aventis); DZ-3358
(Daiichi); FR-182877 (Fujisawa; e.g., WS-9265B); GS-164 (Takeda);
GS-198 (Takeda); KAR-2 (Hungarian Academy of Sciences); B SF-223651
(BASF; e.g., ILX-651 and LU-223651); SAH-49960 (Lilly/Novartis);
SDZ-268970 (Lilly/Novartis); AM-97 (Armad/Kyowa Hakko); AM-132
(Armad); AM-138 (Armad/Kyowa Hakko); IDN-5005 (Indena);
Cryptophycin 52 (e.g., LY-355703); AC-7739 (Ajinomoto; e.g.,
AVE-8063A and CS-39.HC1); AC-7700 (Ajinomoto; e.g., AVE-8062;
AVE-8062A; CS-39-L-Ser.HC1; and RPR-258062A); Vitilevuamide;
Tubulysin A; Canadensol; CA-170 (Curis, Inc.); Centaureidin (e.g.,
NSC-106969); T-138067 (Tularik; e.g., T-67; TL-138067 and
TI-138067); COBRA-1 (Parker Hughes Institute; e.g., DDE-261 and
WHI-261); H10 (Kansas State University); H16 (Kansas State
University); Oncocidin A1 (e.g., BTO-956 and DIME); DDE-313 (Parker
Hughes Institute); Fijianolide B; Laulimalide; SPA-2 (Parker Hughes
Institute); SPA-1 (Parker Hughes Institute; e.g., SPIKET-P);
3-IAABU (Cytoskeleton/Mt. Sinai School of Medicine; e.g., MF-569);
Narcosine (e.g., NSC-5366); Nascapine; D-24851 (Asta medica);
A-105972 (Abbott); Hemiasterlin; 3-BAABU (Cytoskeleton/Mt. Sinai
School of Medicine; e.g., MF-191); TMPN (Arizona State University);
Vanadocene acetylacetonate; T-138026 (Tularik); Monsatrol;
lnanocine (e.g., NSC-698666); 3-IAABE (Cytoskeleton/Mt. Sinai
School of Medicine); A-204197 (Abbott); T-607 (Tuiarik; e.g.,
T-900607); RPR-115781 (Aventis); Eleutherobins (e.g.,
Desmethyleleutherobin; Desaetyleleutherobin; lsoeleutherobin A; and
Z-Eleutherobin); Caribaeoside; Caribaeolin; Halichondrin B; D-64131
(Asta medica); D-68144 (Asta medica); Diazonamide A; A-293620
(Abbott); NPI-2350 (Nereus); Taccalonolide A; TUB-245 (Aventis);
A-259754 (Abbott); Diozostatin; (-)-Phenylahistin (e.g.,
NSCL-96F037); D-62638 (Asta medica); D-62636 (Asta medica);
Myoseverin B; D-43411 (Zentaris; e.g., D-81862); A-289099 (Abbott);
A-318315 (Abbott); HTI-286 (e.g., SPA-110; trifluoroacetate salt)
(Wyeth); D-82317 (Zentaris); D-82318 (Zentaris); SC-12983 (NCI);
Resverastatin phosphate sodium; BPR-OY-007 (National Health
Research Institutes); and SSR-250411 (Sanofi)); goserelin;
leuprolide; triptolide; homoharringtonine; topotecan; itraconazole;
deoxyadenosine; sertraline; pitavastatin; clofazimine;
5-nonyloxytryptamine; vemurafenib; dabrafenib; gefitinib (IRESSA);
erlotinib (TARCEVA); cetuximab (ERBITUX); lapatinib (TYKERB);
panitumumab (VECTIBIX); vandetanib (CAPRELSA); afatinib/BIBW2992;
CI-1033/canertinib; neratinib/HKI-272; CP-724714; TAK-285;
AST-1306; ARRY334543; ARRY-380; AG-1478; dacomitinib/PF299804;
OSI-420/desmethyl erlotinib; AZD8931; AEE726; pelitinib/EKB-569;
CUDC-101; WZ8040; WZ4002; WZ3146; AG-490; XL647; PD153035;
5-azathioprine; 5-aza-2'-deoxycytidine;
17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG); 20-epi-1,25
dihydroxyvitamin D3; 5 ethynyluracil; and BMS-599626.
[0236] In certain embodiments, the combinations described herein
are coadministered with an anti-cancer agent described above, where
the anti-cancer agent has known activity against a particular
cancer (e.g., gemcitibine coadministered with a combination
described herein for treating pancreatic cancer). The anti-cancer
agents above can be approved for use in treating certain
indications (e.g., certain cancers) at concentrations, amounts, and
using treatment regimens known in the art.
[0237] It is understood that modifications which do not
substantially affect the activity of the various embodiments of
this invention are also included within the definition of the
invention provided herein.
HBI-8000 as an Epigenetic Modifier
[0238] Treatment with immune checkpoint inhibitors (ICIs) targeting
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and the
programmed cell death receptor/ligand-1 (PD-1)/(PD-L1) axis is
effective against many cancer types. Not all patients experience a
durable response to ICIs, however, due in part to unresponsiveness
or acquired resistance. Epigenetic changes within the tumor
microenvironment may alter the response to immunotherapy. In
combination with ICIs, class I-selective HDAC inhibitors
reinvigorate immune responses. We used HBI-8000 as an epigenetic
immunomodulator to reprogram the tumor microenvironment from
immunologically cold (nonresponsive) to hot (responsive). We tested
this in preclinical syngeneic mouse tumor immunotherapy models.
[0239] Syngeneic tumors were created in 8-week-old female mice
using the following cell lines: MC38 and CT26 murine colon
carcinoma, RENCA renal adenocarcinoma, A20 B-cell lymphoma, and 4T1
mammary carcinoma cells (MC38 in C57BL/6; CT26, A20, and 4T1 in
BALB/c). Tumors were grown to .about.100 mm.sup.3 prior to
initiating treatment. Mice were treated daily with HBI-8000
(orally), alone or in combination with PD-1, PD-1L, or CTLA-4
antibodies (intraperitoneally). The NanoString nCounter PanCancer
Immune Profiling Panel was used to evaluate the expression of
immune response-related genes in MC38 tumors treated with HBI-8000
alone or in combination with ICIs at several time-points.
[0240] Compared with single-agent ICI therapy, HBI-8000 augmented
the activity of ICI antibodies targeting either PD-1, the PD-1
ligand, or CTLA-4, and significantly increased tumor regression
(p<0.05) in several preclinical models. Gene expression analysis
of the treated MC38 tumors revealed significant changes in mRNA
expression of immune checkpoints, with enhanced dendritic cell and
antigen-presenting cell functions, improved innate and adaptive
immunity scores, and modulation of several important immune
response-relevant genes and major histocompatibility class I and II
molecules.
[0241] These findings show that HBI-8000 mediates epigenetic
modifications in the tumor microenvironment, leading to improved
efficacy of ICIs.
[0242] The MC38 and CT26 syngeneic murine colon carcinomas, RENCA
renal adenocarcinoma, and 4T1 mammary carcinoma cells were obtained
from ATCC (Manassas, Va.), and the A20 cells were obtained from
Covance (Princeton, N.J.). Cells were passaged and maintained using
the protocols provided by the vendors. HBI-8000 was supplied by
HUYA Bioscience International. HBI-8000 (HUYA Bioscience
International) was formulated in 10%
hydroxypropyl-.beta.-cyclodextrin and 10% propylene glycol in
deionized water, pH 2.5. Dosing solutions were prepared fresh
weekly and stored at 4.degree. C. Animals were dosed orally daily
with 50 mg/kg HBI-8000 for 21 days.
[0243] Monoclonal antibodies (mAbs) to mouse PD-1 (clone RPM-14),
PDL-1 (clone (10F.9G2), and CTLA-4 (clone 9H10) were purchased from
Bio-X-Cell (West Lebanon, N.H.). Antibody dosing solutions were
prepared in sterile phosphate-buffered saline on each dosing day,
and stored at 4.degree. C. Mice were intraperitoneally injected
with the PD-1 antibody (Ab) or PD-L1 Ab (10 mg/kg) twice weekly for
3 weeks. CTLA-4 Ab (2.5 mg/kg) was administered intraperitoneally
on days 1, 4, and 7.
[0244] All animal research studies were approved and overseen by
the Institutional Animal Care and Use Committees of Charles River
(MC38, CT26, 4T1) and Champions Oncology (RENCA). All mice obtained
from Charles River (Morrisville, N.C.) were female and 8 weeks old
when the tumors were implanted. For MC38 tumors, C57BL/6 mice were
implanted subcutaneously in the right flank with 1.times.106 MC38
cells (0.1-mL cell suspension). For CT26 tumors, BALB/c mice were
injected subcutaneously in the right flank with 3.times.105 CT26
tumor cells (0.1-mL cell suspension). For A20, BALB/c mice were
implanted subcutaneously in the right flank with 1.times.106 A20
cells (0.1-mL cell suspension). For 4T1, BALB/c mice were implanted
orthotopically in the mammary fat pad with 1.times.106 4T1 cells
(0.1-mL cell suspension). Tumor growth was monitored until reaching
an average volume of 100 mm3, at which time the mice were
randomized into the various treatment groups (day 0). Treatments
were initiated on day 1. Tumor volume was calculated using caliper
measurements according to the following formula: Tumor volume
(mm{circumflex over ( )}3)=(w{circumflex over ( )}2.times.1)/2,
where w=width and l=length (in mm) of the tumor.
[0245] To establish a model of PD-1 antibody failure or stable
disease, 150 mice were initially treated biweekly for 3 weeks with
first-line anti-PD-1 Ab (5 mg/kg, intraperitoneal administration).
Mice bearing tumors that exhibited either slow progression or
stable disease (slow progression was defined as; stable disease was
defined as 3 consecutive measurements with no significant change in
tumor volume) were subsequently re-enrolled into second-line
therapy groups (n=10/group) including Vehicle, HBI-8000, PD-1 Ab,
PD-1 Ab plus HBI-8000, PD-L1 Ab, and PD-L1 Ab plus HBI-8000.
[0246] NanoString nCounter PanCancer Immune Profiling Panel Gene
Expression Studies
[0247] Gene expression studies were carried out using excised MC38
tumors (n=20 animals/treatment) isolated from syngeneic C57BL/6
mice treated for 7, 14, or 17 days with HBI-8000 (50 mg/kg, daily),
anti-PD-1 (10 mg/kg, biweekly), or the combination of
HBI-8000+anti-PD-1 (50 mg/kg, daily, 10 mg/kg, biweekly). At study
termination, tumor samples from the treated mice were collected and
fixed in formalin for 24 h and transferred to EtOH, followed by the
preparation of formalin-fixed paraffin embedded blocks. Tumor
sections (5-10 .mu.m) were prepared from the formalin-fixed
paraffin-embedded blocks, and total RNA was isolated from tissue
scraped from 4 to 6 slides using the protocol recommended by
NanoString Technologies (Seattle, Wash.). The nCounter PanCancer
Immune Profiling panel developed and provided by NanoString
Technologies was initially selected for expression analyses with an
additional 20 genes added as a Panel Plus Codeset. The additional
genes were predicted to be regulated by HBI-8000+/-ICI treatment.
The nCounter assays were performed according to the manufacturer's
instructions using the nCounter FLEX system.
[0248] Gene expression data were analyzed using nSolver software
provided by NanoString Technologies, Inc. Raw data were normalized
to the geometric mean values of the internal synthetic positive
controls and geometric means of the housekeeping genes, as
recommended by the manufacturer. The NanoString Technologies'
nSolver Analysis Software 4.0 generated cell type scores, pathway
scores, heatmaps, and individual gene normalized data from the
nCounter PanCancer Immune Profiling Panel Plus dataset. The cell
type score quantifies cell populations using marker genes for given
cell types; by centering the mean at 0 for each cell type, immune
cell type abundance can be compared on the same scale. The same
method was used to generate immune-relevant pathway scores;
summarizing the data from multiple genes in a pathway into a single
score allowed for comparison between treatments for pathway
analysis.
[0249] Normalized gene expression data for individual genes was
exported from nSolver, annotated with percent of tumor growth
inhibition (% TGI), and then imported into GraphPad Prism 7.04. The
% TGI was used to group animals into 3 categories, as follows:
nonresponders (TGI<25%), partial responders (TGI 25-75%), and
responders (TGI>75%). Gene expression data for each mouse was
color-coded (TGI<25%, TGI 25-75%, TGI>75%) to track gene
expression with tumor response and used to determine if changes in
gene expression correlated with the tumor response.
[0250] Differences in tumor size among groups were assessed using
2-tailed statistical analyses. The statistical tests were conducted
using Prism ver. 7.04 (GraphPad, San Diego, Calif.). The results
are reported as nonsignificant (ns) at P>0.05, significant (*)
at 0.01.ltoreq.P<0.05, very significant (**) at
0.001.ltoreq.P<0.01, and extremely significant (***) at
P<0.001.
[0251] Combining HBI-8000 with antagonist mAbs to mouse PD-1,
PD-L1, and CTLA-4 enhances the antitumor responses and leads to
tumor regression.
[0252] To test whether HBI-8000 augments the antitumor effects of
inhibiting the PD-(L)1 immune checkpoint axis, we treated mice
bearing MC38 syngeneic tumors with HBI-8000, a mouse PD-1 Ab, or
HBI-8000 plus PD-1 Ab (FIG. 8A, B). FIG. 8B shows tumor growth in
individual mice. In addition, we treated MC38 tumor-bearing mice
with HBI-8000, a mouse PD-L1 Ab, or HBI-8000 plus PD-L1 Ab (FIG.
8C, D). Treatment with a single agent (HBI-8000, PD-1 Ab, or PD-L1
Ab) did not significantly affect tumor growth or survival (data not
shown). Tumor regression (i.e., absence of detectable tumor) was
not seen in any of the single agent cohorts, and all tumors
continued to grow throughout the study. In contrast, combining
either the PD-1 Ab or the PD-L1 Ab with HBI-8000 produced a
statistically significant and reproducibly synergistic decrease or
delay in tumor growth and progression (FIG. 8A, C). To corroborate
these results, we extended our investigations to 3 other syngeneic
tumor models. Mice bearing RENCA or A20 tumors were treated with
the same modalities and similar results were generated.
Single-agent HBI-8000, PD-1 Ab (RENCA, FIG. 8E, F), or PD-L1 Ab
(A20, FIG. 8I, J) did not significantly affect either median tumor
growth or survival. As seen in the MC38 model, however, the
combination of either a PD-1 Ab or PD-L1 Ab with HBI-8000 produced
a significant and synergistic decrease or delay in tumor growth and
progression, and importantly, an increase in the number of mice
with tumor regression. Finally, we tested HBI-8000, a mouse CTLA-4
Ab, or HBI-8000 plus CTLA-4 Ab in the CT26 model (FIG. 8G, H).
Similar to ICIs targeting PD-1 and PD-L1, the CTLA-4 Ab alone did
not significantly affect tumor growth. Combining HBI-8000 with
CTLA-4 Ab produced a highly significant delay in tumor progression,
with 20% of tumor-bearing mice experiencing complete
regression.
[0253] In summary, irrespective of the mouse tumor model or ICI Ab,
single-agent therapy did not inhibit/regress tumor growth in any of
the models tested. In all treatments combined with HBI-8000, we
observed tumor regression after treatment, with subsets of tumors
showing a significant delay in progression or outright regression.
The data indicate that combining HDACi HBI-8000 with an ICI Ab was
very efficacious in multiple animal models.
[0254] HBI-8000 epigenetically reprograms the TME and increases the
expression of genes indicating enhanced antigen presentation,
dendritic cell function, and effector cell antitumor
cytotoxicity.
[0255] To investigate the mechanism of action of HBI-8000 in
combination therapy with ICIs, larger groups of mice (n=20/group)
were implanted with MC38 tumors to sufficiently power the
statistical analysis. A baseline no-treatment tumor-bearing group
was killed 1 day before initiating treatment. Mice in each
treatment arm (n=20) were killed at days 7, 14, and 17 post
treatment initiation. The NanoString nCounter PanCancer Immune
Profiling Panel analysis allows for clustering of immune
response-related genes into "gene sets" comprising a collection of
genes selected as being representative of an element of the immune
response (i.e., cell type, pathway), and provides a high level view
of the antitumor response, which is depicted as scatterplots in
FIG. 9A. While all the scores were elevated in the PD-1 Ab plus
HBI-8000 combination agent cohorts, it is noteworthy that a subset
of cell type scores was augmented by either PD-1 Ab or HBI-8000
alone as early as day 7. Scores for exhausted CD8 T cells and
neutrophils were predominantly augmented by the PD-1 Ab. In
contrast, HBI-8000 augmented the scores corresponding to dendritic
cells, macrophages, NK cells, cytotoxic cells, and CD45 cells,
demonstrating that HBI-8000 alone had a profound conditioning or
priming effect on immune-relevant gene expression within the TME,
and suggesting that it reprograms the TME such that ICI therapy is
more effective.
[0256] The de novo generation of new tumor-selective T cell clones
might be a key factor in the response to the PD-1/PD-L1 checkpoint
blockade. Because data from a preliminary study suggested that
HBI-8000, alone or in combination with PD-1 Ab, has profound
effects on the early or priming phase of the immune response, we
investigated changes in the expression of genes associated with
dendritic cell functions, antigen processing, and MHC class II
antigen presentation. Consistently, gene expression analysis in
single agent HBI-8000-treated tumors showed at least partial
co-clustering with the response to the HBI-8000 plus ICI Ab
combination therapy within these gene sets (FIG. 14A). HBI-8000
also co-clustered with combination therapy at the level of MHC
class I antigen expression and presentation, which is important for
effector T cell recognition and killing of tumor cells (FIG. 14B).
Unsupervised hierarchical clustering of the indicated immune cell
type scores vs. treatment and tumor response (FIG. 14A) showed that
gene expression changes representative of these scores were most
notable in the PD-1 Ab plus HBI-8000 combination cohort, and in
responders vs. nonresponders (FIG. 14B). The analysis also
demonstrated segregated clustering of the adaptive vs. innate
response cells types. Not surprisingly, PD-1 Ab plus HBI-8000
combination therapy co-clustered with gene expression sets
representing high response rates (TGI>75%), which was observed
for both adaptive and innate immune cell types. HBI-8000 also
co-clustered with the HBI-8000/PD-1 Ab combination in modulating
the expression of gene sets associated with cytokines, chemokines
and their receptors, and with adaptive immunity-related genes. The
data suggest that the class I/II selective HDACi can epigenetically
modulate gene expression patterns within the TME, which contributes
to multiple facets of the antitumor immune response, leading to the
priming of effector T and B cells, the recognition of tumor cells
by T cells with a consequent shift in the expression of relevant
cytokines and corresponding receptors, and the augmentation of both
innate and adaptive immune responses. Also see heat map data Table
2 below.
TABLE-US-00002 TABLE 2 Heat map data for FIG. 14B Partial APD-1 +
Response APD-1 HBI- Response HBI - vs. No vs. 8000 vs. vs. No 8000
vs. Response Control Control Response Control Gene Cluster 0.7 1.5
1.8 2 2.7 Cytokines and Receptors 0.5 1.5 1.8 2 2.7 Innate 0.5 1.5
1.5 2 2.7 TLR 0.5 1.5 2 2 2.7 Adhesion 0.7 1.5 1.8 1.5 2.7 Cancer
progression 1 1.8 1.8 2 3 Humoral 1 1.5 1.8 1.8 2.8 Macrophage
function -0.5 1.7 2 1.8 2.7 Adaptive -1.5 1.5 1.8 1.8 2.7
Inflammation -1.5 1.5 1.8 1.8 2.8 Transporter Function -1.5 1.5 1.8
1.8 2.8 Leukocyte Function 0.5 1.5 1.8 1.8 2 Apoptosis 0.5 1.3 1.5
1.2 2 Cell cycle -2 1.5 1.3 1.6 2.2 Pathogen Receptors -1.5 1.5 1.3
1.3 2 Senescence 0.5 1 1.5 2 2.5 Interleukin 0.5 1 1.5 2 2.5
Chemokine and Receptors 0.5 1 1.5 2 2.5 TNF superfamily 0.5 1 1.5 2
2.5 B cell Functions 0.5 1 1.7 2.2 2.7 CD molecules 0.7 1.2 1.5 2.2
2.5 T-cell Functions 0.5 1.5 1.5 1.8 1.8 Class I MHC mediated
antigen process 0.5 1.5 1.5 2 1.8 Interferon 1.5 1.5 1.5 2.5 2 NK
cell Function 0.5 1.5 0 2 2.8 Complement pathway -2 1 1.5 0 2 Basic
Cell Function 1.5 1.8 1.8 3 2.8 MHC 1.5 1.8 1.8 2.5 2.8 Antigen
processing 0.5 1.8 1.8 2 2.8 Dendritic cell Functions 1.5 1.5 1.8 4
2.8 MHC class II antigen presentation 1.5 1.8 1 4 2.8 Costimulation
by the CD28 family 1 1.5 3 2 3 Microglial Functions
[0257] HBI-8000 alone or in combination with PD-1 Ab induces
changes in several immune checkpoints within the TME.
[0258] The changes observed in immune checkpoints in the MC38 TME
are shown in FIG. 9B. The data plots are color-coded to represent
the tumor growth inhibition response seen for each individual
animal, set arbitrarily for the purpose of illustration as tumor
growth inhibition >75%, 25% through 75%, or less than 25% to
represent responders, stable disease, and progressers,
respectively. We observed increased expression of the immune
checkpoints PD-1, PD-L1, CTLA-4, and CD86 (CD28L), the expression
levels of which correlated with antitumor efficacy and tumor
regression (FIG. 9B). We also observed statistically significant
changes in the expression of immune checkpoints CD276/B7-H3 and
CD244 (FIG. 9B), as well as lymphocyte activation gene-3 (LAG-3), T
cell immunoreceptor with Ig and ITIM domains (TIGIT),
ecto-5'-nucleotidase (NT5E/CD73), signal regulatory protein .alpha.
(SIRP.alpha.), nuclear factor of activated T cells 4 (NFATC4), and
poliovirus receptor (CD155; FIG. 15). Modulation in the expression
of the above genes indicates a shift from a noninflamed (cold) TME
to an inflamed (hot) TME, and correlated with the antitumor
response in MC38 tumor-bearing mice.
[0259] HBI-8000 alone or in combination with PD-1 Ab induces
changes in immune markers in the TME, including co-stimulators,
markers of cytotoxicity, cytokines and associated receptors, and
MHC.
[0260] In addition to analyzing the effects of HBI-8000, PD-1 Ab,
or their combination on various immune pathways, cell type
functional scores, and immune checkpoint markers, we examined the
effect of HBI-8000, PD-1 Ab, and their combination on a number of
individual genes relevant to either innate or adaptive immunity
(FIGS. 10-12, and Supplemental FIGS. 15, 16). Genes modulated
predominantly by the PD-1 Ab included CD8a (FIG. 11), inducible T
cell costimulator (ICOS/CD278), and CD40/CD40L (FIG. 16). PD-1 Ab
was also the driver for changes in the expression of genes involved
in T cell recruitment, memory, and the CD8 T cell response,
including CXCR6 (FIG. 12), ICOS, CD40, and its ligand CD40L/CD154
(FIG. 16). Our analysis of the nCounter data (FIG. 11) showed
increased T-effector and interferon-y gene scores, which, along
with increases in granzyme B (GZMB) and perforin-1 (PRF1), are
collectively consistent with an enhanced T-effector and
interferon-.gamma. gene, reflecting enhanced existing immune
competency.
[0261] The modulation of many genes occurred, indicating that the
TME inflammation status was dependent exclusively on the
combination of HBI-8000 plus PD-1 Ab. Examples included the
co-stimulator CD86 (FIG. 9B), chemoattractant receptors C--C
chemokine receptor (CCR) 5 (FIG. 10), and CCR1 (FIG. 11), which are
important for initial events in effector T-cell differentiation,
markers of increased tumor reactive effector cells, e.g.,
ectonucleoside triphosphate diphosphohydrolase-1 (ENTPD1/CD39; FIG.
11), PRF1 (FIG. 11), and effector T cell memory precursors
(interleukin 7 receptor [IL7R] and interferon regulatory factor 4
[IRF4], FIGS. 12, 10, respectively). Because HBI-8000 enhances both
CD8 T cell and NK cell activity and functions, relevant genes
modulated predominantly by HBI-8000 are of great interest. HBI-8000
alone, and not PD-1 Ab alone, drove changes in the expression of
4-1BB/CD137 (FIG. 10) and tumor necrosis factor .alpha.
(TNF.alpha.; FIG. 10), interleukin 2 receptor alpha
(IL2R.alpha.)/CD25 and GZMB (FIG. 11), IRF4 (FIG. 10), and
chemokine (C-X3-C motif) receptor 1 (CXC3R1), chemokine (CXC motif)
receptor (CXCR)6, and CXCR3 (FIG. 12), genes that are relevant to
an initial cytokine or CD8 effector response, tumor infiltrating
lymphocyte (TIL) recruitment, effector cell differentiation, and
effector memory.
[0262] Importantly, many genes were modulated by HBI-8000 alone
relatively early (day 7) in the antitumor response (e.g.,
4-1BB/CD137, CD86, TNF.alpha., CCR5, chemokine (C--C motif) ligand
2 (CCL2), IL2R.alpha./CD25 [FIGS. 10, 9b, 10, 10, 10, 11,
respectively], and CCR1 and GZMB [FIG. 11]). Consistent with
reports of HBI-8000 having a positive effect on NK cell functions
and innate immunity, we observed that HBI-8000 alone or combined
with PD-1 Ab modulated the expression of GZMB (FIG. 11), killer
cell lectin like receptor D1 (KLRD1/CD94; FIG. 10), and killer cell
lectin like receptor C2 (NKG2c/KLRC2), natural killer cell granule
protein 7 (NKG7), and killer cell lectin like receptor K1 (KLRK1;
FIG. 16). Finally, and consistent with the upward shifts seen in
all scores relevant for antigen presentation machinery and
supportive of antigen presentation or tumor cell recognition, we
observed increases in the expression of several MHC class I (H2-D1,
H2-K1) and II genes (H2-Aa, H2-Eb1) (FIG. 12), predominantly in
response to HBI-8000 alone (H2-D1, H2-K1) or the combination of
HBI-8000 and PD-1 Ab (H2-Aa, H2-Eb1). This is an important
observation and relevant to the reversal of known mechanisms of
resistance to ICIs, namely the loss of MHC class I and class II
molecules, which impede tumor cell recognition by effector CD8 T
cells, as well the presentation of tumor antigens, including
neoantigens, to naive de novo antitumor immune cells.
[0263] HBI-8000 combined with ICI rescues mice progressing on
single-agent ICI therapy in a model of stable disease leading to
acquired resistance and progression.
[0264] Human cancer patients receiving ICI therapy often experience
a transient response or stable disease, but eventually develop
resistance and progress, a challenge to which major efforts are
directed. Because gene expression data showed that HBI-8000 alone
induced positive changes in a significant number of immune-related
pathway scores and genes, we examined the ability of HBI-8000 to
halt or even reverse progression in mice first treated with
single-agent ICI therapy, alone or in combination with an ICI. To
explore the effect of HBI-8000 plus ICI on acquired resistance, we
developed a model based on the repeated observations that
tumor-bearing mice treated initially (first-line) with single agent
PD-1 Ab or PD-L1 Ab display 4 patterns of growth: approximately 20%
experience rapid progression, approximately 20% experience complete
regression, and approximately 60% experience stable tumor growth
(defined as 3 consecutive tumor volume measurements with no
significant change) or slow progression (relative to rapid growth
and progression), which somewhat approximates the clinical
situation. Using the above model, we treated a large cohort of
tumor-bearing mice with PD-1 Ab alone. Once they reached the
criteria for stable disease or slow progression, they were
randomized into 6 treatment arms as indicated in FIG. 13. We
compared the effect of halting treatment (Vehicle), continuing to
treat with PD-1 Ab, or continuing PD-1 Ab in combination with
HBI-8000. We also compared the effect of mAbs directed against the
reciprocal target, PD-L1, treating mice with PD-L1 Ab, alone or in
combination with HBI-8000. The results of one representative
experiment are shown in FIG. 13. In mice failing PD-1 Ab therapy,
HBI-8000 was modestly active as a second-line therapy, with a
complete response in 2 mice and a partial response in 3 mice at the
end of the study. The second course of PD-1 Ab, however, failed to
significantly affect tumor growth. The modest delay seen in overall
tumor growth provided by treatment with PD-L1 Ab alone was not
significant, but there was 1 complete responder (tumor regression)
and 4 partial responders. A second course of anti-PD-1 therapy
combined with HBI-8000 produced no delay in tumor growth compared
with anti-PD-1 alone. In contrast, combination therapy with
HBI-8000 and anti-PD-L1 significantly (p<0.05) inhibited tumor
growth, indicating that mice progressing on one ICI therapy would
see benefit from an alternative ICI in combination with
HBI-8000.
[0265] Class I-selective HDAC inhibitors reinvigorate immune
response when combined with ICIs. On the basis of recent reports,
HBI-8000 will function as an epigenetic immunomodulator to
reprogram the TME, converting immunologically cold or nonresponsive
tumors to hot or responsive tumors, and tested this hypothesis in
preclinical syngeneic mouse models of tumor immunotherapy. The
ability of HBI-8000 as an HDACi to modulate several immune pathways
important to antitumor immunity indicated that these changes in the
TME epigenome may significantly improve overall responses to ICIs.
This is consistent with accumulating evidence that benzamide class
I-selective HDACi can reprogram the TME epigenome to improve the
antitumor efficacy of ICIs (7, 35-38, 50, 51). Indeed, HBI-8000
combined with any of the 3 ICIs tested (PD-1 Ab, PD-L1 Ab, and
CTLA-4 Ab) displayed enhanced tumor growth inhibition. The nCounter
data suggest that the activity of HBI-8000 extended to both
adaptive and innate immune functionalities. This is consistent with
changes we observed in the expression of several immune checkpoint
molecules associated with an immune T cell-inflamed TME.
Interestingly, the gene expression responses observed followed 3
patterns (Table 1): i) those that were predominantly driven by PD-1
Ab and the combination, ii) those that were predominantly driven by
HBI-8000, and iii) those were modulated primarily or exclusively by
the combination, clearly indicating cooperativity between HBI-8000
and anti-PD-1 in the induction of expression of these genes.
Notably, CD276/B7-H3 and CD244/2B4 (FIG. 9B) as well as CD73/NT5E
(FIG. 15) were modulated primarily by HBI-8000, with little or no
contribution from the addition of PD-1 Ab, again suggestive of an
epigenetic reprograming or "priming" effect on the TME by the
HDACi.
[0266] HBI-8000, either alone or in combination with PD-1 Ab,
altered the expression of several immune checkpoints, many of which
offer potential targets for immunotherapy combinations with
HBI-8000. Interestingly, this appeared to be a cooperative effect
of HBI-8000 and PD-1 Ab in most cases, as neither agent alone was
sufficient. In some cases, however, such as CD276/B7-H3 and
CD244/2B4, increased expression was mediated by HBI-8000 alone.
CD276 is expressed on antigen-presenting cells and plays an
important role in the inhibition of T cell activation and function.
The increase in CD276/B7-H3 expression by HBI-8000 may correlate
with the observed augmentation of dendritic cells and associated
antigen presenting machinery by HBI-8000. It may also affect the
innate immune response and protect tumor cells from NK-mediated
cytotoxicity. CD244 is an immunoregulatory receptor in the
signaling lymphocyte activation molecule (SLAM) family with both
activating and inhibitory properties that seems to function
primarily to mediate inhibitory signaling and T cell exhaustion,
and offers another potential target for immunotherapy.
[0267] Tumor-infiltrating lymphocytes are associated with a
survival benefit in several cancer types and with the response to
immunotherapy. The requirements for maintaining a CD8 T cell TIL
response against human cancer cells may depend on the presence of
stem-like T cells, a distinct subpopulation of CD8 T cells within
tumors. Stem-like T cells are delineated by the expression of TCF1,
IL7R, and IL2R.alpha./CD25 (changes observed in our nCounter data)
as well as the co-stimulatory molecules CD28, CD226, and CD2.
Stem-like T cells terminally differentiate into effector CD8 T
cells, which express higher levels of granzymes, perforin, and
checkpoint molecules. These stem-like T cells reside in dense
antigen-presenting cell niches within the tumor, and tumors that
fail to form these structures are not extensively infiltrated by T
cells. Moreover, patients with progressive disease lack these
immune niches. The increased dendritic cell, MHC class I and II
antigen presentation machinery scores together with an increase in
both MHC class I and II gene expression driven by HBI-8000 may
contribute to the formation and maintenance of these
antigen-presenting cell niches, leading to a CD8 T cell TIL
response in the TME. Indeed, HBI-8000 in combination with PD-1 Ab
or PD-L1 Ab induced an increase in the expression of CD8 in TILs
(FIG. 11), along with higher levels of interferon-.quadrature.,
granzymes, perforin, and checkpoint molecules in treated tumors. It
remains unclear if the increase in immune checkpoint activity in
the combined regimen with HBI-8000 is a consequence of the
epigenetic changes induced directly on tumor or immune cells or the
result of a shift in TME cytokine/chemokine profiles. The current
data, however, suggest that HBI-8000 alters the TME epigenome,
which is necessary for expanding and maintaining both stem-like and
effector CD8 cell populations, resulting in more numerous and
activated CD8 effector cells as reflected by the increase in the
cytotoxic cell, NK CD56dim, CD8 and CD8 vs. exhausted CD8
scores.
[0268] An important and under-appreciated mechanism of adaptive
tumor resistance is the epigenetic or mutational silencing of the
apoptosis machinery. Immunogenic tumor cell death can drive the
priming and clonal expansion of tumor-selective effector T cells,
but it is ultimately the ability of cytolytic cells to kill tumor
cells. HBI-8000 can directly induce cell cycle arrest and apoptosis
in a large number of tumor cells and tumor cell lines [, NCI-60
Panel (data not shown)], but has also been shown to potentiate the
cytotoxic activity of a number of anticancer agents by skewing the
balance of expression toward pro-apoptotic proteins, and thus
triggering the apoptotic response. Based on the current data, as
well as recent reports describing immunomodulatory activities of
other class I selective HDACi, there are at least 2 mechanisms at
play: i) induction of immunomodulatory activities, including
boosting antigen presentation and tumor cell recognition by immune
effector cells and ii) immunogenic cell death, leading to the
release of neoantigens and a potential increase in T cell priming
and de novo generation of new tumor-selective effector T cell
clones. Evidence is accumulating that a robust and durable
antitumor immune response depends on the generation of novel tumor
selective T cell clones and not necessarily the reinvigoration or
reprogramming of exhausted T cells. The observed shift in the CD8
effector T cell to exhausted T cell ratio may reflect an influx of
new tumor-selective T cells.
[0269] Using a model of resistance to ICI and tumor progression, we
found that second-line HBI-8000 in combination with an ICI rescued
a percentage of mice failing ICI therapy (FIG. 13). The ability of
HBI-8000 to enable the immune system to target resistant cancer
cells may be due in part to its putative effect on antigen
presentation and clonal repopulation of the immune response, or its
ability to enhance the reinvigoration of exhausted T cells, or
both. Ultimately, HBI-8000 and other class I-selective HDACi may
epigenetically alter regulatory mechanisms that contribute to
achieving a threshold of immunogenic (proinflammatory) signaling
that is required to elicit an anti-tumor or autoimmune
response.
[0270] In addition to targeting class I HDACs, HBI-8000 inhibits
the activity of class II HDAC10, which is involved in adaptive
resistance to the antitumor immune response. In a recent study,
knockdown of HDAC10 recapitulated the effects of HDAC inhibitors on
immunotherapy biomarkers. Therefore, targeting HDAC10 in addition
to inhibiting HDACs 1, 2, and 3 may provide further support for the
role of HBI-8000 as an epigenetic modulator and primer of the
TME.
[0271] In summary, our data provides a deeper understanding of the
effect of class I HDAC inhibitors on the TME. Consistent with the
preclinical data presented here, clinical data for HBI-8000 in
combination with nivolumab suggest enhancement of activity of
nivolumab by HBI-8000 in patients with melanoma, renal cell
carcinoma, and non-small cell lung cancer
(https://clinicaltrials.gov/ct2/show/NCT02718066), where the
durability and sustainability of response appears elevated even
after treatment cessation. This contrasts with other attempts to
use HDACi with checkpoint inhibitors to generate clinical responses
in patients who have failed prior treatment with ICI
(https://www.ascopost.com/News/59894). The current preclinical data
may further explain the efficacy and durability of HBI-8000 in
combination with nivolumab in the clinical setting. Future studies
will be aimed at better understanding the durability of the
responses elicited by HBI-8000 by interrogating patient samples
through cellular and molecular analysis.
ABBREVIATIONS
[0272] Ab antibody
[0273] CTLA-4 cytotoxic T-lymphocyte-associated protein 4
[0274] CCL2 chemokine (C-C motif) ligand 2
[0275] CCR chemokine (C-C motif) receptor
[0276] CXCR chemokine (CXC motif) receptor
[0277] CXC3R1 chemokine (C-X3-C motif) receptor 1
[0278] ENTPD1 ectonucleoside triphosphate diphosphohydrolase-1
[0279] GZMB granzyme B
[0280] HDAC histone deacetylase
[0281] HDACi histone deacetylase inhibitor
[0282] ICIs immune checkpoint inhibitors
[0283] ICOS inducible T cell costimulator
[0284] IL2Ra interleukin 2 receptor alpha
[0285] IL7R interleukin 7 receptor
[0286] IRF4 interferon regulatory factor 4
[0287] KLRC2 killer cell lectin like receptor C.sub.2
[0288] KLRD1 killer cell lectin like receptor D1
[0289] KLRK1 killer cell lectin like receptor K1
[0290] LAG-3 lymphocyte activation gene-3
[0291] mAb monoclonal antibody
[0292] MHC major histocompatibility complex
[0293] NK natural killer
[0294] NKG7 natural killer cell granule protein 7
[0295] NFATC4 nuclear factor of activated T cells 4
[0296] NT5E ecto-5'-nucleotidase
[0297] PD-1 programmed cell death receptor-1
[0298] PD-L1 programmed cell death receptor-1 ligand 1
[0299] PRF1 perforin-1
[0300] SIRP.alpha. signal regulatory protein .alpha.
[0301] TGI tumor growth inhibition
[0302] TIGIT T cell immunoreceptor with Ig and ITIM domains
[0303] TIL tumor infiltrating lymphocyte
[0304] TME tumor microenvironment
[0305] TNF.alpha. tumor necrosis factor alpha
TABLE-US-00003 Immune System Treatment HBI-8000 Anti-PD1 Combo
Function Genes D 7 D 14 D 17 D 7 D 14 D 17 D 7 D 14 D 17 Innate
Immunity CCL2 + + - - - - + + + Antigen H2-Aa + + - + + - + + +
H2-EB1 + + - + + - + + + Presentation H2-D1 + + + + + + + + + H2-K1
+ + + + + + + - + CCR5 + + - - + - + + + Checkpoint PD-1 - - - + +
+ + + + Molecules PD-L1 + - - + + + + + + CTLA4 + - - + + + + + +
CD86 - - - - - - - - - Co-Stimulatory 4-1BB + + + + - - + + -
Effector Response TNF.alpha. + + + + + - + + + KLRD1 + - - + - - +
+ + IL-2R.alpha. + + - + - - + + + CD8.alpha. - - - + - - + + +
CCR1 + + + + + - + + + ENTPD1 + - - + - - + + + GZMb + + + + + + +
+ + PRF1 + + - + + + + + + Memory T Cells IL-7R + - - - - - + + +
CXCR6 + - - + - + + + + CX3CR1 + + + + + - + + + CXCR3 - - - + - -
+ - +
[0306] Although the invention has been described with reference to
the disclosed embodiments, those skilled in the art will readily
appreciate that the specific examples and studies detailed above
are only illustrative of the invention. It should be understood
that various modifications can be made without departing from the
spirit of the invention. Accordingly, the invention is limited only
by the following claims.
EXAMPLES
[0307] The following examples are included for illustrative
purposes only and are not intended to limit the scope of the
invention.
Example 1
[0308] The rationale for pursuing cancer immunotherapy as a
therapeutic option has been driven by a long history of evidence
that tumors can be recognized as non-self (similar to immune
detection of pathogens like virus-infected cells), rather than as
self (normal tissue). The immune system sees tumors as non-self
mostly through early detection of molecules displayed on tumor
cells that can be recognized as foreign by the immune system, which
ideally becomes activated and effectively attacks and eliminates
the tumor cells. A number of steps must precede an activated immune
response, during which antitumor immune cells can enter
(infiltrate) and engage malignant cells within the now
immunologically inflamed or "hot" tumor. This is commonly referred
to as the Cancer-Immunity Cycle (Chen et al.). Tumor cells however
can adapt over time and evade or become resistant to an antitumor
immune response. A number of such resistance mechanisms are now
known, and the currently approved immunotherapies have been
developed to block some of these resistance mechanisms. For
example, the antibodies directed against the CTLA-4 ligand
(Yervoy.RTM., ipilumumab), the PD-1 receptor (Opdivo.RTM.,
nivolumab; Keytruda.RTM., pembrolizumab, and others) or its ligand
PD-L1 (Tecentriq.RTM., atezolizumab; and others) target these
immune checkpoints and, at least in a portion of patients, relieve
antitumor resistance mediated through the CTLA-4/B7.1 and B7.2
immune checkpoint inhibitory axis or PD-1/PD-L1 checkpoint
inhibitory axis. Although the use of these immune checkpoint
targeting antibodies has resulted in significantly improved patient
benefit and produced remarkable clinical responses in various
cancers, a significant number of patients have tumors that are
either inherently resistant or develop resistance, their tumors
become non-inflamed, lack immune cell infiltrates (TILs) and are
referred to as immunologically "cold" and the disease eventually
progresses. For this reason, rational drug combinations with these
checkpoint inhibitors and other immunomodulating agents are
imperative to improve the rate of durable responses and patient
survival. (See West A C and Johnstone R W. (2014) New and emerging
HDAC inhibitors for cancer treatment. J. Clin. Invest. 124 (1):
30-39).
[0309] HBI-8000 is a histone deacetylase inhibitor (HDACi), which
as an epigenetic regulator that can change the expression of genes,
up or down, without changing the DNA sequence, and therefore has
the ability to alter the expression of genes which are aberrant,
silenced or overexpressed in cancer cells [West and Johnstone,
2014]. Recently there have been several reports describing the
ability of some HDACi (e.g., HBI-8000) to enhance antitumor
immunity through positive effects on a number of the tumor
resistance mechanisms. HDACi's can restore an inflamed or "hot"
immune tumor environment with immune cell infiltrates that become
active and drive antitumor immunity.
[0310] The immunomodulatory effects of the HDACi HBI-8000 on the
tumor micro-environment ("TME") have been well documented. HBI-8000
administration increases the influx of CD8.sup.+ T cells and NK
cells, and improves their function. HBI-8000 administration also
reduces the number and activity of regulatory T cells (TREGs) and
myeloid-derived suppressor cells (MDSCs), and promotes conversion
of M2 (suppressive) to M1 (antitumor) macrophages. HBI-8000
administration also increases PD-1 and PD-L1 expression in "cold"
tumors, along with several other important immune signatures
indicative of cold to hot conversion--this process starts early and
increases over time, as does the number of responders. HBI-8000
drives positive changes in dendritic cell scores and signatures in
the TME, positive changes in antigen presentation, processing, and
display pathways, e.g. MHC Class I and Class II expression
(mechanisms of tumor evasion). HBI-8000 increases the ratio of
active CD8.sup.+ effector T cells to "exhausted" CD8 T cells and
the cytotoxic score and signature, implying re-activation of
inactive tumor selective T cells. HBI-8000 drives changes in the
tumor cells themselves, priming and sensitizing them to the
antitumor immune response--increasing apoptosis scores and
signatures, indicating re-expression of the apoptotic machinery
needed for killing the tumor cells. HBI-8000 driven TME changes
also results in increased presence and activity of NK cells and M1
macrophages (innate immune system), both of which contribute to the
overall antitumor immune response.
[0311] To determine the efficacy of HBI-8000 in combination with
anti-CTLA-4 and anti-PD-1 checkpoint inhibitor antibodies, a study
was conducted using the syngeneic MC38 colon adenocarcinoma in
female C57BL/6 mice. The present study consisted of eleven groups
(n=9 or 8 of female C57BL/6 mice bearing subcutaneous MC38 tumors
(mean volume: 106 mm.sup.3-111 mm.sup.3) on Day 1 of the study,
when dosing was initiated. Vehicle (10%
Hydroxypropyl-(3-Cyclodextrin, 10% Propylene glycol in DI water, pH
2.5) and HBI-8000 (50 mg/kg) were administered orally (p.o.), once
daily for twenty one days (qd.times.21). Anti-CTLA-4 was
administered intraperitoneally (i.p.) at a dose of 2.5 mg/kg on
days 1, 4, and 7. Anti-PD-1 was administered i.p. at 5 mg/kg, twice
a week for two weeks (biw.times.21.
TABLE-US-00004 TABLE 2 Group Number of No. animals Treatment 1
Treatment 2 Treatment 3 1 8 Vehicle 2 9 HBI-8000 50 mg/kg; qdx21 3
8 CTLA-4 mAb 2.5 mg/kg; d 1, d 4, d 7 4 8 PD-1 mAb 5 mg/kg; biw x 2
5 8 CTLA-4 mAb HBI-8000 2.5 mg/kg; 50 mg/kg; d 1, d 4, d 7 qdx21 6
9 CTLA-4 mAb PD-1 mAb 2.5 mg/kg; 5 mg/kg; d 1, d 4, d 7 biw x 2 7 8
CTLA-4 mAb PD-1 mAb HBI-8000 2.5 mg/kg; 5 mg/kg; 50 mg/kg; d 1, d
4, d 7 biw x 2 qdx21 CTLA-4 mAb = hybridoma clone 9H10 PD-1 mAb =
hybridoma clone RMPI-14
[0312] Animals were euthanized when tumor volumes reached 3000
mm.sup.3 or on the last day of the study (Day 43), whichever came
first, and the time to endpoint (TTE) was calculated. Treatment
outcome was determined from percent tumor growth delay (% TGD),
defined as the percent increase in median TTE for treated versus
control mice, with differences between the treatment groups deemed
statistically significant at P<0.05 using logrank survival
analysis. Mice were also monitored for complete regression (CR) and
partial regression (PR) responses. Treatment tolerability was
assessed by body weight (BW) measurements and frequent observation
for clinical signs of treatment-related (TR) side effects.
[0313] The results of these experiments are found in FIG. 1. The
triplet combination therapy comprising a compound of formula I, a
CTLA-4 inhibitor as described herein, and a PD-1 inhibitor as
described herein resulted in statistically significant tumor volume
reduction. The subjects in the triplet combination group also
showed a 40-50% survival rate at the conclusion of the experiments.
(See FIG. 2). Collectively, these results show that the compounds
of formula I enhance the activity of the triplet combination
therapy.
Example 2
[0314] FIG. 3A depicts the probability of progression free survival
("PFS") in terms of months resulting from a combination therapy
comprising compounds of formula I and Nivolumab in melanoma. This
probability was generated from the results published in the New
England Journal of Medicine showing the PFS for patients treated
with Nivolumab monotherapy, ipilimumab monotherapy, or a Nivolumab
plus ipilimumab combination therapy. (See FIG. 3B). The "tailing"
of the plot in FIG. 3B from the combination therapy suggests a
synergistic effect between the Nivolumab and ipilimumab.
[0315] To test this hypothesis, compounds of formula I were
administered in combination with Nivolumab to 20 patients suffering
from melanoma ("MEL") (15 of these patients represented 1.sup.st
line of treatment), 11 patients suffering from renal cell carcinoma
("RCC"), and 13 patients suffering from non-small cell lung cancer
("NSCLC"). Prior to testing, the safety profiles of various dosages
of the compounds of formula I were tested by administering
escalating doses of the compounds of formula I in combination with
the standard dose of nivolumab. A 30 mg BIW was established. The
profile of the 20 MEL patients is depicted in Table 3.
TABLE-US-00005 TABLE 3 Checkpoint-Naive Melanoma Patients (N = 20)
Characteristics Male/Female, n (%) 13/7 (65/35) Median age, years
(range) 64.5 (28-79) <65, n (%) 10 (50) 66-75 6 (30) >75 4
(20) ECOG Score, n (%) 0 13 (65) 1 7 (35) Stage at study entry, n
(%) M1a 5 (25) M1b 12 (60) M1c 3 (15) Elevated LDH, n (%) 2 (10)
Median tumor burden (target 38 (10-167) lesions), mm (range) Median
time since diagnosis, 13.8 (0.7-66.1) months (range) BRAF status, n
(%) Mutated 4 (20) Wildtype 1 (5) Unknown 15 (75) Prior surgery, n
(%) 17 (85) Prior radiation, n (%) 6 (30) Prior systemic therapy, n
(%).sup.a Chemotherapy 1 (5) Immune therapy (excluding 3.sup.b (15)
PD-(L)1 inhibitor) Other 2.sup.c (10) Footnotes: .sup.a2 subjects
received multiple therapies .sup.bipilimumab (2); cellular
immunotherapy (1) .sup.cvemurafenib (1); 1 subject received MEK
inhibitor & BRAF inhibitor
[0316] Imaging studies were performed every 8 weeks to assess tumor
response according to RECIST v1.1. Tumors were observed for
Objective Response Rate (ORR), Disease Control Rate (DCR), and
Standard Disease (SD). The results of the imaging studies are
summarized in Table 4. These results are further detailed in FIG.
4. The waterfall plot of FIG. 4 shows CPI-naive subjects dosed with
compounds of formula I in combination with nivolumab. Each bar
represents a single patient's best response as defined by the sum
of target lesion diameters, measured in terms of change in percent
(baseline is 0% change). Bars falling within +20% increase in tumor
size and -30% decrease in tumor size are considered stable disease.
Further characteristics of the subjects from the study are
summarized in Table 5. And the PFS characterized by metastasis
distribution is summarized in Table 6 while the distribution of PFS
characterized by metastatic sites is summarized in Table 7.
[0317] The group of MEL subjects were analyzed for total time on
treatment regime, termination reason, and best ORR. The status of
the subject's BRAF gene is also noted. The results are summarized
in the swimmer plot of FIG. 5. All treatments were first-line
unless noted with "2L."
TABLE-US-00006 TABLE 4 Phase 1b/2 MEL RCC NSCLC Total Enrolled 20
11 13 44 Evaluable 18 9 8 35 ORR 67% 33% 38% 51% SD 28% 44% 38% 34%
DCR 94% 78% 75% 86%
TABLE-US-00007 TABLE 5 Characteristics of Subjects Days Baseline
Characteristics Days of Tx Days to Treatment BRAF Prior Since last
M Mets HBI- Best PD or D/C Subject Mut PD-L1 Tx Syst Tx LDH
Category Sites 8000 Nivo Response Death Reason 090201 Radiation N/A
Normal M1b Lung 669 687 PR 724+ 090408 Radiation N/A Normal M1b
Lung, 81 57 PR 525+ Node 010716 Wt Neg lpi 121 Normal M1a Nodes
487+ 487+ PR 487+ 090304 None N/A Normal M1b Lung 459 419 SD 459+
090724 Wt None N/A Normal M1c Pancreas 427+ 427+ PR 427+ 090723 Pos
Excision N/A Normal M1b Lung, 40 253 PR 383+ Node 090731 Wt None
N/A Normal M1a Nodes 361+ 361+ PR 361+ 090727 Wt None N/A Normal
M1b Lung 109 336 CR 355+ 090721 None N/A High M1c Liver, 169 141 PR
343+ Lung 090733 V600E None N/A Normal M1b Lung 341+ 341+ CR 341+
090732 None N/A Normal M1c Lung, 187 295 PR 292+ PI Adrenal,
decision Node 010719 unknown None N/A Normal M1c Liver, 97 169 SD
197 Clin PD Lung, Nodes 090406 Radiation N/A Normal M1a Muscle 109
46 CR 178 PI discretin, PD date = death 090722 None N/A High M1b
Lung 31 169 SD 168+ not included in ORR due to <8 weeks of
HBI-8000 090711 Surg N/A Normal M1c Liver 110 183 SD 168 Resection
090730 Pos None N/A Normal M1a Soft 163 169 SD 163 D/C due to
tissue clinical progression 090728 Pos None N/A Normal M1b Lung,
137 141 SD 137 D/C due to Soft clinical tissue progression 090302
vemuraf/ 30 Normal M1b Lung 109 127 PR 110 TIL 090717 Pos TKI 334
Normal M1b Lung 81 85 PD 57
TABLE-US-00008 TABLE 6 PFS by Metastasis Distribution PFS (days) N
= 19 M1a M1b M1c >400 n = 5 1 3 1 200-400 n = 6 1 3 2 100-200 n
= 7 2 3 2 <100 n = 1 1
TABLE-US-00009 TABLE 7 Distribution of PFS by Metastatic Sites PFS
Days M Stage N >400 200-400 100-200 <100 M1a 4 1 1 2 0 M1b 10
3 3 3 1 M1c 5 1 1 2 0
Example 3
[0318] Additional studies were conducted to test the effect of a
combination therapy comprising compounds of formula I and nivolumab
in melanoma patients with prior immune checkpoint treatment. In
these studies, 8 patients were evaluable. 2 of the 8 patients
showed PR. 4 of the 8 patients showed SD. Further, the ORR was 25%
in this group, while the DCR was 75%. A patient from this study had
a tumor that was NRAS positive. Further, the patient had high LDH
and an unknown level of PD-L1 expression. This patient had
extensive prior treatment including surgery, radiation,
ipilimumab+nivolumab, nivolumab maintenance, T-vec and
pembrolizumab, TIL+high dose IL-2. This patient achieved a PR in 54
days and was on treatment for over 249 days. This PR is suggestive
of epigenetic effects on the tumor. The characteristics and outcome
summaries for the patients in this study are summarized in Table 8.
Based on these results, combined with the data collected from
melanoma-naive patients (FIG. 5), it is recommended that the
combination treatment of the compounds of formula I and nivolumab
is used as a second-line treatment for patients having failed
BRAF/MEK inhibitors (in patients with a BRAF mutant).
TABLE-US-00010 TABLE 8 Patients Characteristics and Outcome
Summary-Checkpoint Inhibitor Treated Prior Systemic Days Baseline
Characteristics Days of Tx Days to Treatment BRAF PD- Tx (best
Since Last M Mets HBI- Best PD or D/C Subject Mut L1 response) Syst
Tx LDH Category Sites 8000 Nivo Response Death Reason 010717 Wt Ipi
x 4 (PR) N/A Normal M1a Node, 98 112 SD 112 Clinical Pembro X soft
progression. 29 (SD) tissue Died of CHF in hospice 090720 V600R Ipi
(PD) N/A Normal M1c Liver, 55 57 PD 55 Pembro (PD) Node Dabra/Tram
(PD) Fludarabine/ cyclophospamide/ IL-2 (PD) Vemur/cobi (toxicity)
090729 V600E Adj 8 months Normal M1a Soft 444+ 444+ PR 444+
Interferon tissue TIL Vemurafenib Neoadj Pembro 090737 Wt Adj 4
months High M1a Renal 199 209 PR 358+ Interferon hilar Nivo/ipi +
mass nivo Pelvic T-Vec mass Pembro Sub-cu TIL + high mass dose node
IL-2 090738 V600K Dabra/Tram 14 months Normal M1c Nodes, 201 225 SD
243 Death not Pembro 2 liver related to years Ipi/ study pembro X4
treatment Pembro 090739 unknown Pembro (SD) N/A Normal M1a Soft 103
113 SD 133+ Pt withdrew Pembro + tissue from study ipi (SD) nodules
to pursue other treatment
Example 4
[0319] The tolerability of the compounds of formula I, nivolumab,
and a combination of the compounds of formula I and nivolumab were
tested. The Phase 2 clinical dosage of 30 mg BIW of the compounds
of formula I was administered. Among 63 subjects with adverse event
("AE") data available, Treatment Emergent Adverse Event ("TEAE"),
52% were considered related to treatment ("TRAE"). Among TRAEs, 47%
were associated with the combination of the compounds of formula I
and nivolumab ("NIVO"), 39% compounds of formula I alone, and 14%
NIVO alone. Less frequent TRAEs associated with NIVO alone were
lipase increase (n=6), rash (n=10), TSH increase (n=5), amylase
increase (n=4). Further, among Grade 3 AEs, only fatigue, headache,
diarrhea, nausea, vomiting were symptomatic--others were
asymptomatic. Grade 3 fatigue in one subject responded to a low
dose oral steroid. The fatigue in another subject was resolved by
withholding drug only--no intervention necessary. Grade 3 diarrhea
was resolved with an over counter drug. Grade 3 headache responded
to over counter drug and did not recur on subsequent dosings. In
addition, nausea and vomiting responded to oral drug. No AE was
difficult to manage in oncology practice, and none caused medical
concerns by investigators. Other asymptomatic AEs were
abnormalities of blood test, most did not require treatments. When
counting AEs with symptoms, only 4 out of 20 subjects experienced
clinically significant AEs on nivo+compounds of formula I. The
findings of this study are summarized in Table 9 below.
TABLE-US-00011 TABLE 9 Tolerability Profile HBI-8000 + NIVO TRAE
.gtoreq. 5% frequency and number of subject n (% of N) Association
Compounds of Compounds of Formula I + NIVO Formula I NIVO AE Term
G1-2 G3 G4 G1-2 G3 G4 G1-2 G3 G4 Fatigue 24 (38) 4 (6) 0 0 0 0 0 0
0 Diarrhea 19 (30) 3 (5) 0 0 0 0 4 (6) 1 (2) 0 Lymphocyte decrease
6 (10) 1 (2) 0 0 0 0 0 0 0 Neutrophil decrease 4 (6) 2 (3) 0 8 (13)
5 (8) 1 (2) 0 0 0 WBC decrease 6 (10) 1 (2) 0 11 (17) 1 (2) 0 0 0 0
Platelet decrease 10 (16) 0 0 23 (37) 3 (5) 0 0 0 0 Anemia 0 0 0 14
(22) 1 (2) 0 0 0 0 Hypophospatemia 0 0 0 6 (10) 4 (6) 0 0 0 0
Example 5
[0320] Immune gene activation in response to administration of the
compounds of formula I, a PD-1 inhibitory antibody, and a
combination of the compounds of formula I and a PD-1 inhibitory
antibody was examined using an MC38 tumor model. The results are
summarized in FIG. 6A. These results show that the combination of
the compounds of formula I and a PD-1 inhibitory antibody
synergistically activated immune gene expression in the tumor
microenvironment. FIG. 6B summarizes the improvement on survival
amongst the experimental group treated with the combination therapy
compared to the compounds of formula I alone or the PD-1 inhibitory
antibody alone.
Example 6
[0321] The compounds of formula I were used as a monotherapy for
relapsed or refractory peripheral T-cell lymphoma ("RR/PTCL"). A
dosage of 40 mg biw was approved for this study. A summary of the
results is found in Table 10. These results were compared to
efficacy/history benchmarks for several known treatments for
RR/PTCL (see Table 11). The time after prior treatment was 96 days
(vs. 222 days for romidepsin P2 trial). The estimated PFS and OS of
the experiment are found in FIGS. 7A-B. For these results, the PD
date was due to investigator judgement. The median PFS (months) was
7.6.
TABLE-US-00012 TABLE 10 Example 6 Results Summary Patients Numbers
Phase 2 Enrolled Total 55 Evaluable Total 43 Complete Responses 4
Partial Responses 16 Stable Disease 12 ORR 46% DCR 74%
Pharmaceuticals and Medical 30% Devices Agency ("PMDA") Target
ORR
TABLE-US-00013 TABLE 11 Efficacy vs. Historical Benchmarks for
RR/PTCL Treatments RR/PTCL Treatment ORR Epidaza (China) (PMS) 28%
(35%) Forodesine 22% Pralatrexate 45% Romidepsin 43%
Example 7
[0322] The compounds of formula I were used as a monotherapy for
relapsed or refractory aggressive adult T-cell lymphoma ("RR/ATL").
A dosage of 40 mg biw was approved for this study. A summary of the
results is found in Table 12. These results were compared to
efficacy/history benchmarks for several known treatments for RR/ATL
(see Table 13). The time after prior treatment was 88 days (vs. 234
days for lenalidomide P2 trial). All patients had received
mogamulizumab ("moga") (lenalidomide ORR in moga patients was
18%).
TABLE-US-00014 TABLE 12 Example 7 Results Summary Patients Numbers
Phase 2 Enrolled Total 23 Evaluable Total 20 Partial Responses 8
Stable Disease 4 ORR 40% DCR 60% Pharmaceuticals and 30% Medical
Devices Agency ("PMDA") Target ORR
TABLE-US-00015 TABLE 13 Efficacy vs. Historical Benchmarks for
RR/ATL Treatments RR/PTCL Treatment ORR Compounds of Formula I
Phase I 75% Mogamulizumab 50% Lenalidomide 42%
[0323] While preferred embodiments of the present invention have
been shown and described herein, it will be obvious to those
skilled in the art that such embodiments are provided by way of
example only. Numerous variations, changes, and substitutions will
now occur to those skilled in the art without departing from the
invention. It should be understood that various alternatives to the
embodiments of the invention described herein may be employed in
practicing the invention. It is intended that the following claims
define the scope of the invention and that methods and structures
within the scope of these claims and their equivalents be covered
thereby.
* * * * *
References